RARE DISEASE
Intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy
Intrahepatic cholestasis of pregnancy
Synonyms: Gravidic intrahepatic cholestasis, Pregnancy-related cholestasis, Recurrent intrahepatic cholestasis of pregnancy
Synonyms: Gravidic intrahepatic cholestasis, Pregnancy-related cholestasis, Recurrent intrahepatic cholestasis of pregnancy
Synonyms: Gravidic intrahepatic cholestasis, Pregnancy-related cholestasis, Recurrent intrahepatic cholestasis of pregnancy
Drug discovery
0
drugs
With orphan designations
Overview
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by pruritus and elevated serum bile acids, typically presenting in the third trimester. Driven by hormonal, genetic, and environmental factors, ICP increases risks of preterm labor (30–60%), fetal distress, and stillbirth (3% with bile acids ≥100 µmol/L). Management focuses on ursodeoxycholic acid, fetal monitoring, and timed delivery [1][5][7][12][15].
Burden
Maternal: Severe pruritus (99%), gestational diabetes (25.7%), preeclampsia, postpartum hemorrhage [2][6][15]
Fetal/neonatal: Preterm birth (44.5%), meconium aspiration, respiratory distress, stillbirth risk escalating with bile acids [5][7][15]
Long-term: Maternal hepatobiliary/cardiovascular risks, offspring metabolic/immune dysregulation [6][8][15]
Therapies
First-line: Ursodeoxycholic acid (10–15 mg/kg/day) to reduce pruritus and improve liver function [3][7][10][16]
Monitoring: Serial bile acid levels, liver function tests, and fetal surveillance (e.g., NSTs) [3][7][12]
Delivery: Timed at 36–39 weeks based on bile acid severity (≥100 µmol/L warrants ≤36 weeks) [3][7][12][15]
Categories: rare gynecological and obstetric diseases, rare hepatic diseases
Research Papers
666 drug discovery papers about Intrahepatic cholestasis of pregnancy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
666 drug discovery papers about Intrahepatic cholestasis of pregnancy, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-01 | Nanocellulose Alleviates Intrahepatic Cholestasis of Pregnancy via Gut Microbiota‐Mediated Bile Acid Homeostasis (Adv. Sci. 45/2026)
Cellulose Nanofibers This cover illustration highlights a promising gut microbiota-targeted strategy for intrahepatic cholestasis of pregnancy (ICP). Dietary cellulose nanofibers (CNF) enrich beneficial microbes and modulate gut-liver farnesoid X receptor (FXR) signaling. This cascade reduces maternal systemic bile acid burdens and improves offspring survival, identifying CNF as a biosafe, translationally viable intervention for managing gestational bile acid disorders. More details can be found in the Research Article by Yuhao Zhang, Xiaojing Dong, Ting-Li Han, and co-workers (DOI: 10.1002/advs.202518337).
2026-07-29 | MOTS-c attenuates placental vascular endothelial cell apoptosis in intrahepatic cholestasis of pregnancy by inhibiting K33-linked deubiquitination of BACH1
Intrahepatic cholestasis of pregnancy (ICP) is a gestational liver disorder characterized by impaired placental vascular architecture, leading to placental dysfunction and fetal growth restriction. Our prior work demonstrated that the transcription repressor BACH1 modulates SLC25A51 expression to regulate placental injury under ICP conditions. MOTS-c, a mitochondria-originated peptide, participates in vascular homeostasis, yet its biological functions within the placental vasculature during ICP have not been fully characterized. Clinical analyses revealed significantly reduced MOTS-c protein levels in both maternal serum and placental tissues from ICP patients. In a cholic acid-induced murine model of ICP, MOTS-c administration promoted placental angiogenesis and inhibited apoptosis of placental vascular endothelial cells. These protective effects were recapitulated in vitro , where MOTS-c attenuated oxidative stress and apoptosis in human umbilical vein endothelial cells (HUVECs) exposed to taurocholic acid. Mechanistically, biotinylated MOTS-c pull-down coupled with mass spectrometry identified BACH1 as a direct binding partner; subsequent functional validation demonstrated that MOTS-c binds competitively to the D560 residue of BACH1, thereby displacing the deubiquitinase USP7 and promoting K33-linked polyubiquitination and proteasomal degradation of BACH1. Consequently, MOTS-c-mediated BACH1 depletion relieves transcriptional repression of SLC25A51, enhancing mitochondrial NAD + import, biogenesis, and redox resilience. Importantly, BACH1 overexpression abolished MOTS-c–induced protection in HUVECs, confirming the functional dependency of MOTS-c on this axis. In vivo , MOTS-c treatment in CA-induced ICP mice significantly improved key offspring developmental parameters-including birth weight, placental efficiency, and neonatal survival. Collectively, these findings establish MOTS-c as a placenta-targeted endogenous regulator that ameliorates ICP-associated placental vascular pathology and adverse perinatal outcomes via modulation of the BACH1/SLC25A51 signaling axis.
2026-07-24 | Adult-Onset BAAT p.Glu401Asp Mutation Linking Intrahepatic Cholestasis of Pregnancy to FXR-SREBP Dysregulation.
Intrahepatic cholestasis of pregnancy (ICP) affects 0.5-5.6 % of pregnancies and involves bile acid transport defects (ABCB11, ABCB4, ATP8B1). BAAT mutations classically cause neonatal familial hypercholanemia type 3 (FHCA3), with five previously identified pathogenic variants in the catalytic domains. We report a rare adult-onset homozygous BAAT missense mutation (c.1203G>T; p.Glu401Asp) in a 41-year-old Indian woman with third-trimester ICP, postpartum-persistent hypercholanemia, and severe hypertriglyceridemia. This novel BAAT substitution occurs at codon 401 (C-terminal, non-catalytic), yielding conflicting in silico predictions (CADD: 22.5 pathogenic vs. REVEL: 0.211 benign). However, classified as a Variant of Uncertain Significance, its homozygosity and phenotypic correlation support plausibility, pending family segregation, bile acid profiling, or functional assays. Proposedly unconjugated primary bile acids impair ileal FXR activation, thereby disrupting FGF19-SHP-mediated repression of SREBP-1c lipogenesis, a process compounded by insulin resistance. This case represents a rare adult BAAT-ICP association and BAAT-related FXR-SREBP dysregulation, expanding the low-GGT cholestasis spectrum per EASL guidelines. Glycocholic acid and FXR agonists may offer targeted therapies.
2026-07-22 | Mechanistic Basis and Translational Potential of Traditional Chinese Medicine in the Treatment of Cholestasis: A Narrative Review.
Cholestasis results from impaired bile formation, secretion, or flow and contributes to heterogeneous hepatobiliary disorders, including primary biliary cholangitis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, cholestatic drug-induced liver injury, and cholestasis-associated fibrosis. Persistent bile acid retention drives hepatocyte and cholangiocyte injury, immune activation, gut-liver axis disruption, and fibrogenesis. Traditional Chinese medicine (TCM) has been investigated as a multi-component therapeutic approach, but its evidence strength and translational readiness remain uncertain. To synthesize mechanistic, clinical, and translational evidence on TCM-based interventions for cholestasis and identify evidence gaps relevant to future development. PubMed, Web of Science Core Collection, CNKI, Wanfang, VIP, and SinoMed were searched for publications from 1 January 2016 to 25 January 2026, supplemented by backward citation chasing. A sensitivity search of CNKI, Wanfang, VIP, and SinoMed was performed to reduce language bias. Eligible studies were mapped by cholestatic condition or model, intervention type, study design, mechanistic domain, clinical relevance, and evidence strength. Eighty studies were included in the core evidence set. The evidence base was dominated by preclinical animal, in vitro, omics, pharmacokinetic, quality-control, and toxicology studies, with limited mature clinical evidence. Recurrent mechanisms involved FXR-centered bile acid homeostasis, transporter regulation, inflammatory and immune pathways, oxidative stress and regulated cell death, fibrogenic signaling, and gut-liver axis modulation. Clinical evidence was most developed for intrahepatic cholestasis of pregnancy, where adjunctive TCM plus ursodeoxycholic acid was associated with improvements in bile acids and pruritus. However, heterogeneity in formula composition, trial quality, endpoint selection, and safety reporting limits inference, particularly for maternal-fetal outcomes. Evidence for other cholestatic indications remains limited or largely preclinical. TCM provides pathway-linked therapeutic hypotheses and candidate compounds for cholestasis, but high-confidence translation requires standardized products, exposure-response characterization, causal target validation, robust safety and herb-drug interaction assessment, and adequately powered disease-specific trials using clinically meaningful endpoints.
2026-07-03 | Maternal and neonatal outcomes of intrahepatic cholestasis of pregnancy in twin pregnancies: a systematic review and meta-analysis.
Intrahepatic cholestasis of pregnancy (ICP) is linked with adverse perinatal outcomes; however, its impact in twin pregnancies remains unclear. This systematic review and meta-analysis aimed to evaluate maternal and neonatal outcomes in twin pregnancies complicated by ICP. A comprehensive search of PubMed, Embase, Web of Science, and Scopus was conducted from inception to 14 February 2026. Cohort studies comparing twin pregnancies with and without ICP were included. Random-effects meta-analyses were performed to assess maternal and neonatal outcomes reported by at least three studies. Seven retrospective cohort studies were included. ICP in twin pregnancies was associated with increased risk of cesarean delivery, preeclampsia, and gestational diabetes mellitus. Preterm birth (PTB) <37 weeks was significantly increased with ICP in both crude and adjusted analysis. Mean gestational age was significantly reduced, and birthweight was lower in ICP. ICP was strongly associated with meconium-stained amniotic fluid and increased neonatal intensive care unit (NICU) admission. However, no significant association was noted between ICP and stillbirth, small-for-gestational age and postpartum hemorrhage. ICP in twin pregnancies is associated with PTB and increased maternal and neonatal morbidity. Current evidence is derived mostly from crude data and from a limited number of studies with high inter-study heterogeneity.
gene therapies
2026-06-29 | Bile acid-induced TBG depletion promotes trophoblast apoptosis via local thyroxine insufficiency in intrahepatic cholestasis of pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) is characterized by bile acid accumulation, placental dysfunction, and adverse perinatal outcomes. However, there is currently no reliable tool to predict the occurrence of severe ICP or its associated complications, and its pathophysiology remains incompletely understood. The objective of this study was to identify more sensitive and specific biomarkers for the clinical diagnosis, early prediction, and prognostic assessment of adverse outcomes in ICP, and to explore the biological relevance of the identified pathway at the maternal-fetal interface. We performed integrated serum metabolomic-proteomic analysis, followed by trimester-specific clinical validation, placental tissue analysis, in vitro trophoblast experiments, and in vivo validation in an estrogen-induced ICP rat model. Exploratory multi-omics analysis highlighted the thyroxine-binding globulin-thyroxine (TBG-T4) axis, related to thyroid hormone transport and availability, as a biologically relevant pathway in ICP. Although total and free T4 remained within physiological reference ranges, circulating TBG, total T4, and free T4 were significantly reduced across pregnancy in women with ICP and were associated with biochemical cholestasis, earlier delivery, and lower neonatal birth weight. Mechanistic analyses showed that reduced TBG availability was associated with decreased local T4 availability and enhanced trophoblast apoptosis under bile acid stress. In the ICP rat model, Ad-TBG-mediated TBG overexpression partially restored thyroid hormone homeostasis, attenuated placental and hepatic injury, and improved fetal growth and survival. These findings identify disruption of the TBG-T4 axis as a mechanistic link between cholestatic stress, impaired thyroid hormone availability, and trophoblast apoptosis in ICP.
2024-09-12 | Genetic issues in ICP.
Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disorder with variable global incidence. Genetic susceptibility, combined with hormonal and environmental influences, contributes to ICP aetiology. Adverse pregnancy outcomes linked to elevated serum bile acids highlight the importance of comprehensive risk assessment. ABCB4 and ABCB11 gene variants play a significant role in about 20% of severe ICP cases. Several other genes including ATP8B1, NR1H4, ABCC2, TJP2, SERPINA1, GCKR and HNF4A have also been implicated with ICP. Additionally, ABCB4 variants elevate the risk of drug-induced intrahepatic cholestasis, gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis and abnormal liver function tests. Genetic variations, both rare and common, intricately contribute to ICP susceptibility. Leveraging genetic insights holds promise for personalised management and intervention strategies. Further research is needed to elucidate variant-specific phenotypic expressions and therapeutic implications, advancing precision medicine in ICP management.
2022-05-31 | A minimal bile salt excretory pump promoter allows bile acid-driven physiological regulation of transgene expression from a gene therapy vector
Bile acid (BA) homeostasis is mainly regulated by bile salt excretory pump (BSEP), a hepatocyte transporter that transfers BAs to the bile. BSEP expression is regulated by BA levels through activation of farnesoid X receptor transcription factor, which binds to the inverted repeat (IR-1) element in the BSEP promoter. Gene therapy of cholestatic diseases could benefit from using vectors carrying endogenous promoters physiologically regulated by BAs, however their large size limits this approach, especially when using adeno-associated viral vector (AAV) vectors.We evaluated the functionality and BA-mediated regulation of minimal versions of human and mouse BSEP promoters containing IR-1 using AAV vectors expressing luciferase. Unexpectedly, a minimal mouse BSEP promoter (imPr) showed higher BA-mediated expression and inducibility than a minimal human promoter (ihPr) or than full-length BSEP promoters in human hepatic cells. In addition, in mice receiving an AAV8 vector carrying imPr promoter-driven luciferase expression was efficiently regulated by administration of a BA-enriched diet. Interestingly, this vector also expressed significantly higher luciferase levels in Abcb4-/- mice, which have high levels of BAs, compared to wild type mice, or to mice receiving a vector containing the luciferase gene downstream of the constitutive alpha-1 antitrypsin promoter. In contrast, the AAV vector containing ihPr showed very low luciferase expression with no inducibility. Finally, we optimized imPr by adding three IR-1 repeats at its 5' end. This new promoter provided higher levels of luciferase than imPr both in vitro and in vivo.The imPr could represent a useful tool for gene therapy approaches in which physiological BA regulation is desired.
2019-05-16 | Bioinformatics‑based identification of key pathways and candidate genes for estrogen‑induced intrahepatic cholestasis using DNA microarray analysis
Estrogen‑induced intrahepatic cholestasis (EIC) has increased incidence during pregnancy, and within women taking oral contraception and postmenopausal hormone replacement therapy. However, the pathology underlying EIC is not well understood. The aim of the present study was to identify key pathways and candidate genes in estrogen‑induced intrahepatic cholestasis (EIC) that may be potential targets for diagnosis and treatment. A whole‑genome microarray (4x44K) analysis of a 17α‑ethinylestradiol (EE)‑induced EIC rat liver model was performed. Bioinformatics‑based methods were used to identify key pathways and candidate genes associated with EIC. The candidate genes were validated using a reverse transcription quantitative polymerase chain reaction assay. A total of 455 genes were differentially expressed (P<0.05 and fold change >2.0) following EE treatment, including 225 downregulated genes and 230 upregulated genes. Sulfotransferase family 1E member 1, cytochrome P450 family 3 subfamily A member 2, carbonic anhydrase 3, leukotriene C4 synthase and ADAM metallopeptidase domain 8 were the 5 candidate genes identified to be differentially expressed and involved in the metabolism of estrogens and bile acids and the regulation of inflammation and oxidative stress. The Analyses of Gene Ontology enrichment, Kyoto Encyclopedia of Genes and Genomes pathways and protein‑protein interaction network associated‑modules identified several key pathways involved in the homeostasis of lipids and bile acids and in AMPK, p53 and Wnt signaling. These key pathways and candidate genes may have critical roles in the pathogenesis of EIC. In addition, reversing the abnormal expression of candidate genes or restoring the dysfunction of key pathways may provide therapeutic opportunities for patients with EIC.
2018-10-24 | ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum
Abstract ATP-binding cassette subfamily B member 4 (ABCB4) is a phospholipid translocator at the canalicular membrane of the hepatocyte, which “flops” phosphatidylcholine into bile. Dysfunction of this transporter due to ABCB4 gene variants can cause liver diseases and has been called ABCB4 deficiency. Several diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3), low phospholipid-associated cholelithiasis (LPAC), a subgroup of patients developing intrahepatic cholestasis of pregnancy (ICP), drug-induced liver injury and chronic cholangiopathy with biliary fibrosis and cirrhosis were attributed to ABCB4 deficiency and characterized in the past decade. LPAC and ICP are usually caused by monoallelic variants, whereas patients affected by PFIC3 are homozygous or compound heterozygous carriers of ABCB4 variants. Treatment with ursodeoxycholic acid is often effective, but as the more severe forms of ABCB4 deficiency progress, nevertheless, new diagnostic and therapeutic approaches are warranted. Current functional classifications for ABCB4 deficiency–associated mutations can guide the development of novel genotype–based targeted pharmacotherapies for these conditions. Recently, increasing evidence from genome-wide association studies is emerging on associations of ABCB4 variants with hepatobiliary malignancies.
cell therapies
2025-11-26 | Plasmapheresis for Suspected Drug-Induced Liver Injury During Pregnancy: A Multidisciplinary Diagnostic and Therapeutic Challenge
Acute liver injury during pregnancy is rare and predominantly associated with pregnancy-related conditions including acute fatty liver of pregnancy; Hemolysis, Elevated Liver Enzymes and Low Platelets syndrome; intrahepatic cholestasis of pregnancy; and preeclampsia. Drug-induced liver injury (DILI) is a less common and often overlooked cause of acute liver injury in pregnant patients. A literature search on acute liver injury during pregnancy and therapeutic plasma exchange was conducted, revealing the most common causative factors and syndromes. A 39-year-old woman was diagnosed with acute liver injury in the 23rd week of her third pregnancy and, upon extensive differential diagnoses, a suspicion of DILI occurred after the use of methyldopa. Methyldopa, the drug of choice for the treatment of hypertensive disorders of pregnancy, has a high safety profile for the developing fetus and is well tolerated by pregnant women, yet, in susceptible individuals, a hepatotoxic effect may occur. The drug was discontinued and symptomatic treatment with ursodeoxycholic acid and prednisone was implemented with marginal effect. Upon a multidisciplinary joint consultation, plasmapheresis procedures were introduced, granting a significant improvement in the patient’s liver function and enabling the continuation of the pregnancy. Plasmapheresis treatment was safely and effectively used for the first time in the therapeutic process in a pregnant patient with DILI. Interdisciplinary cooperation of specialists with gastroenterology, nephrology, and obstetrics expertise is crucial to achieving a timely diagnosis and begin effective treatment for pregnant patients with acute liver injury.
2025-10-10 | Probiotic VSL#3 alleviates intrahepatic cholestasis of pregnancy by upregulating farnesoid X receptor-fibroblast growth factor 15 through regulation of the gut microbiota.
Intrahepatic cholestasis of pregnancy (ICP) poses significant risks to both maternal and fetal health, and treatment options remain limited. This study investigated the efficacy and underlying mechanisms of VSL#3 in alleviating ICP. Clinical fecal and blood samples were collected from 26 patients with ICP and 21 healthy pregnant women. The gut microbiota composition was analyzed using 16S rRNA sequencing. To further explore causality, we established a fecal microbiota transplantation-ICP mouse model using fecal samples from ICP patients, as well as an estrogen-induced ICP mouse model. Compared with healthy pregnant women, ICP patients exhibited a distinct gut microbiota profile, characterized by an increased abundance of Bacteroides and Alistipes. Serum FGF19 levels were significantly lower in ICP patients, showing a negative correlation with liver function markers, such as serum total bile acid (TBA), and a positive correlation with beneficial genera including Bifidobacterium, Ruminococcus, Blautia, Dorea, Eubacterium (hallii group) and Ruminococcus (torques group). VSL#3 treatment in mice alleviated ICP manifestations by improving liver histopathology, reducing TBA and alanine aminotransferase levels, increasing FGF15 concentrations, and enhancing fetal outcomes. These beneficial effects were abolished by co-administration of the FXR antagonist Z-guggulsterone, confirming the role of FXR signaling. In conclusion, VSL#3 alleviated ICP by modulating the gut microbiota to activate the FXR-FGF15 axis, thereby reducing bile acid synthesis and improving maternal and fetal outcomes.
2024-04-01 | Severe Elevated Bile Acids in Early Pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) typically presents in the second half of pregnancy. Severe ICP is associated with increased risk of stillbirth. Little is known regarding elevated bile acids in the first trimester. We present a case of severely elevated bile acids in the first trimester, resistant to conservative management, in a patient with pre-existing cholestatic liver disease and aortic valve disease requiring anticoagulation. Therapeutic plasma exchange was used. In those with pre-existing cholestatic disease, early bile acid elevation is likely distinct from ICP, and conservative strategies may not be useful. In addition, therapeutic enoxaparin appears safe in therapeutic plasma exchange.
2023-11-29 | Roseburia intestinalis relieves intrahepatic cholestasis of pregnancy through bile acid/FXR-FGF15 in rats.
Previous research has demonstrated significant differences in intestinal flora between pregnant women with intrahepatic cholestasis of pregnancy (ICP) and healthy pregnant women. The objective of our study is to identify the key bacteria involved in ICP rats and explore the underlying mechanism. We established an ICP rat model and collected rat feces for metagenomic sequencing and found that Roseburia intestinalis (R.I) is the key bacteria in ICP. Transplantation of R.I improved phenotypes associated with ICP through the bile acid/farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) signaling pathway. We used the FXR antagonist Z-Guggulsterone (Z-Gu) to verify the key role of FXR in ICP and found that Z-Gu reversed the benefits of R.I on ICP rats. Our research highlights the important role of intestinal flora in the pathogenesis of ICP and provides a novel approach for its treatment.
2023-05-18 | Principles of treatment of intrahepatic cholestasis of pregnant women
BACKGROUND:Intrahepatic cholestasis of pregnancy occupies a leading place in the structure of hepatoses associated with pregnancy. As with many other diseases that debut during gestation, all the symptoms of intrahepatic cholestasis of pregnancy disappear after delivery and have no consequences for the mother, unlike, for example, acute fatty degeneration of the liver. However, the fetal prognosis remains serious due to the high incidence of preterm birth and the toxic effect of bile components on the developing fetus, which both lead to perinatal complications. Especially fatal is the situation when intrahepatic cholestasis of pregnancy is combined with intrauterine infection, placental insufficiency, severe preeclampsia, diabetes mellitus, or other extragenital pathology. Until recently, it was believed that the only correct solution for intrahepatic cholestasis of pregnancy development was early delivery. Only in recent decades, attempts have been made to therapeutic correction of this pathology in order to prolong pregnancy to full term and reduce the frequency of perinatal complications. So far, tangible results have been achieved with the use of ursodeoxycholic acid preparations and the introduction of efferent methods of therapy into obstetric practice.
AIM:The aim of this study was to develop optimal schemes for pathogenetic therapy of intrahepatic cholestasis of pregnancy using hepatoprotectors from the ursodeoxycholic acid group, as well as ademetionine, essential phospholipids, and membrane plasmapheresis.
MATERIALS AND METHODS:This study included 150 pregnant women with intrahepatic cholestasis of pregnancy. Group I (n= 50) comprised patients who were treated only with ursodeoxycholic acid. Group II (n= 50) included individuals who were given combined drug therapy with ursodeoxycholic acid, ademetionine, and essential phospholipids. Group III (n= 50) consisted of women whose treatment included efferent therapies (membrane plasmapheresis) in combination with ursodeoxycholic acid or ademetionine preparations. All pregnant women before the start of therapy were determined the blood levels of bile acids, total and direct bilirubin, and transaminases (alanine aminotransferase, aspartate aminotransferase). Blood parameters were monitored once every seven days. All the patients were also monitored for the condition of the fetus (fetometry, dopplerometry, cardiotocography).
RESULTS:The use of ursodeoxycholic acid not combined with other hepatoprotectors (group I) was possible only in cases of increased blood levels of bile acids of not more than 40 mmol/L, preparations of ademetionine and essential phospholipids as monotherapy being ineffective. With an increase in the blood levels of bile acids of more than 40 mmol/L and transaminases by two to three or more times from the upper limit of the norm (group II), the most effective was the combined use of ursodeoxycholic acid, ademetionine and essential phospholipid preparations. The most significant decrease in the blood levels of bile acids and hepatic cytolysis parameters (transaminases) was observed when plasmapheresis was used in combination with ursodeoxycholic acid or ademetionine (group III).
CONCLUSIONS:The choice of treatment regimen depends on the level of increase in bile acids and the severity of cytolytic syndrome. With an increase in the level of bile acids to 40 mmol/L, ursodeoxycholic acid preparations can be used only. With an increase in bile acid level of more than 40 mmol/L, the complex use of the above hepatoprotectors is necessary. The most effective treatment regimen is the use of membrane plasmapheresis in combination with ursodeoxycholic acid or ademetionine.
proteins
2026-04-21 | Peptidomics Landscape of Intrahepatic Cholestasis of Pregnancy and its Molecular Mechanism Investigation.
Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that poses substantial health risks to both mother and fetus. However, its pathogenesis remains unclear. Our previous study highlighted the significance of ferroptosis in ICP. To fully elucidate the pathogenesis of ferroptosis related to ICP and identify new therapeutic strategies, we used nanoscale liquid chromatography coupled with tandem mass spectrometry analysis in an in vitro model of ICP induced by taurocholic acid to investigate the peptidomics of ICP. The peptide profile successfully revealed 27,527 peptides, of which 1,180 were related to ferroptotic differentially expressed peptides in the screened ICP. Through comprehensive bioinformatics analyses, combined with 3,783 ICP and 1,518 ferroptosis targets, we identified 20 hub genes and molecular functions, including ubiquitin protein ligase binding, which may be involved in the development of ICP. Four potential bioactive peptides were selected through in silico analysis and further verified using in vitro, molecular docking, and molecular dynamics studies. Peptides DLTGIPPAPR and PRLPEEWSQW have the potential to enhance trophoblast viability and modulate important genes, such as HSPB1, HSPA5, and SQSTM1, which could be beneficial in managing ICP by inhibiting ferroptosis. Our findings provide crucial insight into the pathophysiological mechanisms underlying ICP.
2026-01-30 | Study on the mechanism of DLK1 in placenta of intrahepatic cholestasis of pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, prominently characterized by elevated serum bile acids and adverse fetal outcomes. This study focused on the expression of Delta-like 1(DLK1) in the placenta of patients with ICP,along with the alterations in placental blood vessels and function. The bile acid - induced ICP cell model was utilized to clarify the impact of DLK1 on the function of trophoblast cells under the pathological context of ICP. Human placental tissues were subjected to immunohistochemical staining, immunofluorescence, Western blotting (WB)and qPCR. These techniques were employed to analyze the expression of DLK1 and functional status of blood vessels in the ICP placenta. An ICP cell model was established using Taurocholate acid (TCA). WB, qPCR, and reactive oxygen species (ROS) assays were conducted to detect the effects of TCA and DLK1 on trophoblast function. The effects of TCA and DLK1 on endothelial cell function were evaluated through migration and tube formation assays. The results indicated that the expression levels of DLK1, placental growth factor, and angiogenesis factor were significantly lower in the human ICP placenta. Concomitantly, the Notch1 signaling pathway was found to be inhibited. The addition of DLK1 to the ICP cell model improved the function of the cells, and the supernatant of the trophoblast cells also promoted the migration and tube formation ability of HUVECs. In the ICP placenta, the expression of DLK1 is reduced, accompanied by a decline in placental blood vessels and placental function. Exogenous addition of DLK1 can activate the Notch1 pathway, promote placental angiogenesis and mitigate oxidative damage.
2025-08-13 | Multi-omics characterization of autophagy-related molecular features in intrahepatic cholestasis of pregnancy†.
Despite the increasing body of evidence that autophagy implicate in intrahepatic cholestasis of pregnancy (ICP), we are still far from a mechanistic understanding of the autophagy in ICP pathogenesis. In this study, we performed untargeted lipidomics, scRNA-seq, and RNA-seq data to systematically demonstrate the lipid alterations, cells and gene expression closely related to autophagy in placenta. These results were also verified by tissue, cell, and animal experiments. We confirmed that autophagy played a pivotal role in ICP, autophagy-related lipids including PE (38:2e) and PE (54:5) had a good diagnostic value. Autophagy genes were mainly concentrated in villous cytotrophoblast (VCT), extravillous trophoblast (EVT), and macrophage. VCT was found increased while EVT decreased in ICP. In the subcluster analysis of VCT, VCT-EVT, the precursor cells of EVT, was significantly reduced. In the subcluster analysis of EVT, EVT2 cells with epithelial migration and regulatory functions were significantly reduced. Furthermore, autophagy gene TNFSF10 was decreased in ICP, while supplementation of soluble TNFSF10 could restore the expression of TNFSF10 in ICP cell model, which alleviated the autophagic damage and improved the invasion and migration ability of trophoblast cells. Our study established the causal linkage between autophagy and ICP, providing a potential therapeutic avenue to improve trophoblast function accounting for ICP by targeting autophagy gene TNFSF10.
2025-08-09 | Mendelian Randomization Study of Sex Hormone Binding Globulin and Its Influence on Adverse Pregnancy Outcomes.
The relationship between sex hormone-binding globulin (SHBG) levels and the risk of adverse pregnancy outcomes (APOs) remains controversial. A two-sample Mendelian randomization (MR) study was performed to clarify the causality of SHBG on the risk of APO. Significant single-nucleotide polymorphisms (SNPs) associated with SHBG levels were obtained from the genome-wide association study (GWAS) in the European population. Summary statistics of the number of spontaneous miscarriages, preeclampsia, gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy (ICP), and female infertility were utilized as the outcome. The causality was examined primarily by inverse-variance weighted (IVW), along with MR-Egger regression, weighted median estimator, and weighted mode method. Based on the IVW model, every genetically predicted standard deviation (SD) increase in SHBG levels was causally associated with 0.023 SDs decrease of the number of spontaneous miscarriages (Beta ± SE: -0.023 ± 0.010, p = 0.018), 11.3% decrease of the risk of preeclampsia (OR = 0.887, 95% CI: 0.806-0.977, p = 0.015), 17% decrease of the risk of GDM (OR = 0.830, 95% CI: 0.753-0.914, p = 0.000), 23.6% decrease of the risk of ICP (OR = 0.764, 95% CI: 0.584-0.999, p = 0.049), and 14% decrease of the risk of infertility (OR = 0.860, 95% CI: 0.777-0.951, p = 0.003). Our study indicated that the increased levels of SHBG could significantly reduce the risk of APO. SHBG may be helpful as the indicator for preconception risk assessment and pregnancy risk monitoring. These findings are limited to European and require further validation in diverse populations.
2022-08-19 | The effectiveness of small heterodimer partner and FGF 19 levels in prediction of perinatal morbidity in intrahepatic cholestasis of pregnancy.
Fibroblast growth factor 19 (FGF19) and small heterodimer partner (SHP) are molecules responsible for controlling serum bile acid levels. We designed this study for evaluating the effects of FGF 19 and SHP in intrahepatic cholestasis of pregnancy (ICP). Fifty-six pregnant women having ICP and 20 healthy pregnant women were included in the study. The patients were followed up until delivery in terms of pregnancy-related morbidity/mortality. Serum FGF 19 and SHP levels were determined by enzyme-linked immunosorbent assay (ELISA). Serum FGF 19 and SHP levels were significantly higher in the patient group compared to the control group (p: .04, p: .003, respectively). In ROC analysis, SHP level above 1995 ng/L was found effective in predicting the need for neonatal intensive care unit (ICU) follow-up with 53.8% sensitivity and 77.8% specificity. High SHP levels were correlated with perinatal morbidity, mortality and neonatal ICU hospitalisation.Impact StatementWhat is already known on this subject? Itching, elevated serum transaminase and serum total bile acid (TBA) levels are the most important clinical and biochemical findings of intrahepatic cholestasis of pregnancy (ICP). Fibroblast growth factor 19 (FGF19) and small heterodimer partner (SHP) are molecules - responsible for controlling serum bile acid levels. ICP is associated with preterm labour, asphyxia, foetal distress, stillbirth and preeclampsia.What do the results of this study add? Serum FGF 19 and SHP levels were significantly higher in the patient group compared to the control group. High SHP level was found effective in predicting the need for neonatal intensive care unit and showed a negative correlation with birth week and birth weight.What are the implications of these findings for clinical practice and/or further research? Checking SHP levels can help to predict perinatal mortality and morbidity. Treatments to be developed through the mechanism of action of FGF 19 and SHP can be promising in the treatment of ICP and other cholestatic liver diseases.
other
2026-04-22 | PIP2 Accumulation in the Spongiotrophoblast Drives Trophoblast Apoptosis in Intrahepatic Cholestasis of Pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by elevated maternal bile acids and an increased risk of adverse fetal outcomes. Although placental dysfunction is a key contributor to ICP pathogenesis, the underlying mechanisms remain incompletely understood. Here, we combined a Sprague-Dawley rat model of ICP with spatial metabolomics to delineate region-specific metabolic alterations within the placenta. Multivariate analysis revealed distinct metabolic signatures between ICP and control placentas, with pronounced reprogramming in trophoblast-enriched regions. Differential metabolite and pathway analyses identified significant perturbations in glycerophospholipid metabolism, pyruvate metabolism, phospholipase D signaling, and the tricarboxylic acid cycle. Notably, phosphatidic acid (PA) was broadly elevated, whereas its downstream product phosphatidylinositol 4,5-bisphosphate (PIP2) exhibited spatially restricted accumulation in trophoblasts. Mechanistically, taurocholic acid exposure in HTR-8/SVneo cells induced upregulation of PIP5K1, leading to PIP2 accumulation and increased trophoblast apoptosis via disruption of the Bcl-2/Bax balance. Silencing of PIP5K1 restored PIP2 homeostasis and attenuated apoptosis. Importantly, these molecular alterations were recapitulated in placental tissues from ICP patients, confirming activation of the PIP5K1-PIP2 axis in vivo. Collectively, our findings identify a spatially resolved PA-PIP5K1-PIP2 lipid signaling cascade that links bile acid-induced metabolic stress to trophoblast apoptosis and placental dysfunction in ICP.
2025-09-19 | MicroRNA-940 Induces Apoptosis of HTR8-S/Vneo Cells in Intrahepatic Cholestasis of Pregnancy by Regulating RhoA.
The expression of microRNA is likely to be closely associated with intrahepatic cholestasis of pregnancy (ICP). This study aimed to investigate the potential mechanisms underlying miR-940/RhoA-induced apoptosis in HTR8-S/Vneo cells in ICP. In this study, 80 pregnant women diagnosed with ICP were recruited, with healthy pregnant women as controls. RT-qPCR was utilized to quantify the expression levels of miR-940 and RhoA. Cell proliferation was evaluated using the CCK-8 assay, while flow cytometry was employed to assess cell apoptosis. The dual-luciferase reporter assay confirmed the targeting relationship between miR-940 and RhoA. miR-940 expression was significantly elevated in the ICP group. ROC curve analysis demonstrated that miR-940 exhibited high diagnostic accuracy for ICP. Cell proliferation assays indicated that miR-940 negatively regulates cell proliferation. Apoptosis experiments revealed that low levels of miR-940 inhibited apoptosis. The dual-luciferase reporter assay confirmed that miR-940 targeted RhoA, establishing a negative correlation between them. The reversed experiment demonstrated that while the downregulation of miR-940 promoted cell proliferation and inhibited apoptosis, these effects were partially reversed when RhoA expression was suppressed. In conclusion, miR-940 played a crucial role in regulating cell proliferation and apoptosis, and it held potential as a therapeutic target for inhibiting the apoptosis of HTR8-S/Vneo cells in ICP.
2024-04-19 | Exosomes from Intrahepatic Cholestasis of Pregnancy Induce Cell Apoptosis Through the miRNA-6891-5p/YWHAE Pathway.
Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse pregnancy outcomes; however, the underlying mechanisms are not fully understood. This study aimed to determine the role of exosomal miR-6891-5p in placental trophoblast dysfunction in ICP and identify new biomarkers for ICP diagnosis. Serum samples were collected from ICP patients and healthy pregnant women, and serum exosomes were extracted and identified. Fluorescent dye labeling of exosomes and cell-verified cell phagocytosis were performed. In vitro experiments were conducted by adding taurocholic acid to simulate the ICP environment. Cell proliferation and apoptosis levels were detected using flow cytometry and the cell counting kit-8 assay. Mimics were constructed to overexpress miR-6891-5p in cells, and the binding site between miR-6891-5p and YWHAE was verified using luciferase reporter genes. miR-6891-5p expression was significantly decreased in serum exosomes of ICP patients. Co-culturing with exosomes derived from ICP patients' serum (ICP-Exos) decreased HTR-8/SVeno cell proliferation and increased apoptosis levels. miR-6891-5p upregulation in HTR-8/SVeno cells significantly increased cell viability and reduced cell apoptosis levels, as determined by the cell counting kit-8 assay and flow cytometry. A double luciferase assay confirmed that miR-6891-5p affected the expression of the downstream YWHAE protein. This study indicates that serum exosomes from ICP patients can impact the apoptosis of placental trophoblast HTR-8/SVeno cells through the miR-6891-5P/YWHAE pathway and can serve as specific molecular markers for ICP diagnosis.
2022-07-12 | Immune Dysfunction Mediated by the ceRNA Regulatory Network in Human Placenta Tissue of Intrahepatic Cholestasis Pregnancy.
Pregnancy-related intrahepatic cholestasis (ICP) is a serious complication with adverse perinatal outcomes of preterm labor, fetal distress, or stillbirth. As a result, it is important to investigate and identify the potential critical pathogenic mechanisms of ICP. First, we collected the placental tissues from the ICP with placental weight and fetal birth weight loss for the whole transcriptome sequencing. Then we analyzed the differentially expressed (DE) circRNAs (DEcircRNAs) by SRPBM, DElncRNAs by FRKM, DEmiRNAs by TPM, and DEmRNAs by TPM and RSEM. Based on differential expression of term pregnancy placental tissues from pregnancies impacted by ICP (n=7) as compared to gestational aged matched control tissues (n=5), the circ/lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) regulatory networks were constructed. The ceRNA regulatory networks covered 3,714 events, including 21 DEmiRNAs, 36 DEcircRNAs, 146 DElncRNAs, and 169 DEmRNAs. According to the functional analysis, ICP complications were linked to the immune system, signal transduction, endocrine system, cell growth and death, and transport and catabolism. Further evidence suggested that the expression of immune-related genes KLRD1, BRAF, and NFATC4 might have a potential ceRNA mechanism by individual lncRNA sponging miR372-3p, miR-371a-3p, miR-7851-3p, and miR-449a to control downstream the level of TNF-α, IFN-γ, and IL-10, thereby regulating the pathophysiology of ICP. Furthermore, our results were validated by the qRT-PCR, western blotting and ELISA assays. In conclusion, this study is the first to evaluate placental ceRNA networks in pregnancies affected by ICP, showing alterations in immune regulatory networks which may impact fetal and placental growth. Overall our these data suggest that the ceRNA regulatory network may refine biomarker predictions for developing novel therapeutic approaches in ICP.
2022-06-03 | Circ_0060731 mediated miR-21-5p-PDCD4/ESR1 pathway to induce apoptosis of placental trophoblasts in intrahepatic cholestasis of pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy complication. However, the pathogenesis of ICP is currently unclear. We analyzed the placenta samples of 10 normal and 10 ICP pregnant women. the expressions of circ0060731, miR-21-5p, and their downstream target genes PDCD4, ESR1, and apoptotic protein cleaved-caspase3 were detected in the cell model. The expression of Circ_0060731, PDCD4, ESR1, and caspase-3 was higher in the ICP placenta tissue than in the control group, and the expression of miR-21-5p was lower in the ICP group than in the control group. In HTR8/Svneo cells treated with TCA, the expression/levels of Circ_0060731, PDCD4, ESR1, and caspase-3 were significantly higher in the ICP group than in the control group, and miR-21-5p was significantly lower in the ICP group than in the control group. Lentiviral knockdown of miR-21-5p significantly increased the expressions of its downstream genes of PDCD4 and ESR1, and also increased cell apoptosis. Overexpression of miR-21-5p significantly reduced the expression of PDCD4 and ESR1 and reduced cell apoptosis. The dual-luciferase experiment showed that both PDCD4 and ERS1 were the target genes of miR-21-5p. Circ_0060731 mediated miR-21-5p-PDCD4/ESR1 pathway could induce apoptosis of placental trophoblasts in intrahepatic cholestasis of pregnancy.
small molecules
2026-08-01 | Nanocellulose Alleviates Intrahepatic Cholestasis of Pregnancy via Gut Microbiota‐Mediated Bile Acid Homeostasis (Adv. Sci. 45/2026)
Cellulose Nanofibers This cover illustration highlights a promising gut microbiota-targeted strategy for intrahepatic cholestasis of pregnancy (ICP). Dietary cellulose nanofibers (CNF) enrich beneficial microbes and modulate gut-liver farnesoid X receptor (FXR) signaling. This cascade reduces maternal systemic bile acid burdens and improves offspring survival, identifying CNF as a biosafe, translationally viable intervention for managing gestational bile acid disorders. More details can be found in the Research Article by Yuhao Zhang, Xiaojing Dong, Ting-Li Han, and co-workers (DOI: 10.1002/advs.202518337).
2026-07-29 | MOTS-c attenuates placental vascular endothelial cell apoptosis in intrahepatic cholestasis of pregnancy by inhibiting K33-linked deubiquitination of BACH1
Intrahepatic cholestasis of pregnancy (ICP) is a gestational liver disorder characterized by impaired placental vascular architecture, leading to placental dysfunction and fetal growth restriction. Our prior work demonstrated that the transcription repressor BACH1 modulates SLC25A51 expression to regulate placental injury under ICP conditions. MOTS-c, a mitochondria-originated peptide, participates in vascular homeostasis, yet its biological functions within the placental vasculature during ICP have not been fully characterized. Clinical analyses revealed significantly reduced MOTS-c protein levels in both maternal serum and placental tissues from ICP patients. In a cholic acid-induced murine model of ICP, MOTS-c administration promoted placental angiogenesis and inhibited apoptosis of placental vascular endothelial cells. These protective effects were recapitulated in vitro , where MOTS-c attenuated oxidative stress and apoptosis in human umbilical vein endothelial cells (HUVECs) exposed to taurocholic acid. Mechanistically, biotinylated MOTS-c pull-down coupled with mass spectrometry identified BACH1 as a direct binding partner; subsequent functional validation demonstrated that MOTS-c binds competitively to the D560 residue of BACH1, thereby displacing the deubiquitinase USP7 and promoting K33-linked polyubiquitination and proteasomal degradation of BACH1. Consequently, MOTS-c-mediated BACH1 depletion relieves transcriptional repression of SLC25A51, enhancing mitochondrial NAD + import, biogenesis, and redox resilience. Importantly, BACH1 overexpression abolished MOTS-c–induced protection in HUVECs, confirming the functional dependency of MOTS-c on this axis. In vivo , MOTS-c treatment in CA-induced ICP mice significantly improved key offspring developmental parameters-including birth weight, placental efficiency, and neonatal survival. Collectively, these findings establish MOTS-c as a placenta-targeted endogenous regulator that ameliorates ICP-associated placental vascular pathology and adverse perinatal outcomes via modulation of the BACH1/SLC25A51 signaling axis.
2026-07-24 | Adult-Onset BAAT p.Glu401Asp Mutation Linking Intrahepatic Cholestasis of Pregnancy to FXR-SREBP Dysregulation.
Intrahepatic cholestasis of pregnancy (ICP) affects 0.5-5.6 % of pregnancies and involves bile acid transport defects (ABCB11, ABCB4, ATP8B1). BAAT mutations classically cause neonatal familial hypercholanemia type 3 (FHCA3), with five previously identified pathogenic variants in the catalytic domains. We report a rare adult-onset homozygous BAAT missense mutation (c.1203G>T; p.Glu401Asp) in a 41-year-old Indian woman with third-trimester ICP, postpartum-persistent hypercholanemia, and severe hypertriglyceridemia. This novel BAAT substitution occurs at codon 401 (C-terminal, non-catalytic), yielding conflicting in silico predictions (CADD: 22.5 pathogenic vs. REVEL: 0.211 benign). However, classified as a Variant of Uncertain Significance, its homozygosity and phenotypic correlation support plausibility, pending family segregation, bile acid profiling, or functional assays. Proposedly unconjugated primary bile acids impair ileal FXR activation, thereby disrupting FGF19-SHP-mediated repression of SREBP-1c lipogenesis, a process compounded by insulin resistance. This case represents a rare adult BAAT-ICP association and BAAT-related FXR-SREBP dysregulation, expanding the low-GGT cholestasis spectrum per EASL guidelines. Glycocholic acid and FXR agonists may offer targeted therapies.
2026-07-22 | Mechanistic Basis and Translational Potential of Traditional Chinese Medicine in the Treatment of Cholestasis: A Narrative Review.
Cholestasis results from impaired bile formation, secretion, or flow and contributes to heterogeneous hepatobiliary disorders, including primary biliary cholangitis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, cholestatic drug-induced liver injury, and cholestasis-associated fibrosis. Persistent bile acid retention drives hepatocyte and cholangiocyte injury, immune activation, gut-liver axis disruption, and fibrogenesis. Traditional Chinese medicine (TCM) has been investigated as a multi-component therapeutic approach, but its evidence strength and translational readiness remain uncertain. To synthesize mechanistic, clinical, and translational evidence on TCM-based interventions for cholestasis and identify evidence gaps relevant to future development. PubMed, Web of Science Core Collection, CNKI, Wanfang, VIP, and SinoMed were searched for publications from 1 January 2016 to 25 January 2026, supplemented by backward citation chasing. A sensitivity search of CNKI, Wanfang, VIP, and SinoMed was performed to reduce language bias. Eligible studies were mapped by cholestatic condition or model, intervention type, study design, mechanistic domain, clinical relevance, and evidence strength. Eighty studies were included in the core evidence set. The evidence base was dominated by preclinical animal, in vitro, omics, pharmacokinetic, quality-control, and toxicology studies, with limited mature clinical evidence. Recurrent mechanisms involved FXR-centered bile acid homeostasis, transporter regulation, inflammatory and immune pathways, oxidative stress and regulated cell death, fibrogenic signaling, and gut-liver axis modulation. Clinical evidence was most developed for intrahepatic cholestasis of pregnancy, where adjunctive TCM plus ursodeoxycholic acid was associated with improvements in bile acids and pruritus. However, heterogeneity in formula composition, trial quality, endpoint selection, and safety reporting limits inference, particularly for maternal-fetal outcomes. Evidence for other cholestatic indications remains limited or largely preclinical. TCM provides pathway-linked therapeutic hypotheses and candidate compounds for cholestasis, but high-confidence translation requires standardized products, exposure-response characterization, causal target validation, robust safety and herb-drug interaction assessment, and adequately powered disease-specific trials using clinically meaningful endpoints.
2026-07-03 | Maternal and neonatal outcomes of intrahepatic cholestasis of pregnancy in twin pregnancies: a systematic review and meta-analysis.
Intrahepatic cholestasis of pregnancy (ICP) is linked with adverse perinatal outcomes; however, its impact in twin pregnancies remains unclear. This systematic review and meta-analysis aimed to evaluate maternal and neonatal outcomes in twin pregnancies complicated by ICP. A comprehensive search of PubMed, Embase, Web of Science, and Scopus was conducted from inception to 14 February 2026. Cohort studies comparing twin pregnancies with and without ICP were included. Random-effects meta-analyses were performed to assess maternal and neonatal outcomes reported by at least three studies. Seven retrospective cohort studies were included. ICP in twin pregnancies was associated with increased risk of cesarean delivery, preeclampsia, and gestational diabetes mellitus. Preterm birth (PTB) <37 weeks was significantly increased with ICP in both crude and adjusted analysis. Mean gestational age was significantly reduced, and birthweight was lower in ICP. ICP was strongly associated with meconium-stained amniotic fluid and increased neonatal intensive care unit (NICU) admission. However, no significant association was noted between ICP and stillbirth, small-for-gestational age and postpartum hemorrhage. ICP in twin pregnancies is associated with PTB and increased maternal and neonatal morbidity. Current evidence is derived mostly from crude data and from a limited number of studies with high inter-study heterogeneity.
gene therapies
2026-06-29 | Bile acid-induced TBG depletion promotes trophoblast apoptosis via local thyroxine insufficiency in intrahepatic cholestasis of pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) is characterized by bile acid accumulation, placental dysfunction, and adverse perinatal outcomes. However, there is currently no reliable tool to predict the occurrence of severe ICP or its associated complications, and its pathophysiology remains incompletely understood. The objective of this study was to identify more sensitive and specific biomarkers for the clinical diagnosis, early prediction, and prognostic assessment of adverse outcomes in ICP, and to explore the biological relevance of the identified pathway at the maternal-fetal interface. We performed integrated serum metabolomic-proteomic analysis, followed by trimester-specific clinical validation, placental tissue analysis, in vitro trophoblast experiments, and in vivo validation in an estrogen-induced ICP rat model. Exploratory multi-omics analysis highlighted the thyroxine-binding globulin-thyroxine (TBG-T4) axis, related to thyroid hormone transport and availability, as a biologically relevant pathway in ICP. Although total and free T4 remained within physiological reference ranges, circulating TBG, total T4, and free T4 were significantly reduced across pregnancy in women with ICP and were associated with biochemical cholestasis, earlier delivery, and lower neonatal birth weight. Mechanistic analyses showed that reduced TBG availability was associated with decreased local T4 availability and enhanced trophoblast apoptosis under bile acid stress. In the ICP rat model, Ad-TBG-mediated TBG overexpression partially restored thyroid hormone homeostasis, attenuated placental and hepatic injury, and improved fetal growth and survival. These findings identify disruption of the TBG-T4 axis as a mechanistic link between cholestatic stress, impaired thyroid hormone availability, and trophoblast apoptosis in ICP.
2024-09-12 | Genetic issues in ICP.
Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disorder with variable global incidence. Genetic susceptibility, combined with hormonal and environmental influences, contributes to ICP aetiology. Adverse pregnancy outcomes linked to elevated serum bile acids highlight the importance of comprehensive risk assessment. ABCB4 and ABCB11 gene variants play a significant role in about 20% of severe ICP cases. Several other genes including ATP8B1, NR1H4, ABCC2, TJP2, SERPINA1, GCKR and HNF4A have also been implicated with ICP. Additionally, ABCB4 variants elevate the risk of drug-induced intrahepatic cholestasis, gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis and abnormal liver function tests. Genetic variations, both rare and common, intricately contribute to ICP susceptibility. Leveraging genetic insights holds promise for personalised management and intervention strategies. Further research is needed to elucidate variant-specific phenotypic expressions and therapeutic implications, advancing precision medicine in ICP management.
2022-05-31 | A minimal bile salt excretory pump promoter allows bile acid-driven physiological regulation of transgene expression from a gene therapy vector
Bile acid (BA) homeostasis is mainly regulated by bile salt excretory pump (BSEP), a hepatocyte transporter that transfers BAs to the bile. BSEP expression is regulated by BA levels through activation of farnesoid X receptor transcription factor, which binds to the inverted repeat (IR-1) element in the BSEP promoter. Gene therapy of cholestatic diseases could benefit from using vectors carrying endogenous promoters physiologically regulated by BAs, however their large size limits this approach, especially when using adeno-associated viral vector (AAV) vectors.We evaluated the functionality and BA-mediated regulation of minimal versions of human and mouse BSEP promoters containing IR-1 using AAV vectors expressing luciferase. Unexpectedly, a minimal mouse BSEP promoter (imPr) showed higher BA-mediated expression and inducibility than a minimal human promoter (ihPr) or than full-length BSEP promoters in human hepatic cells. In addition, in mice receiving an AAV8 vector carrying imPr promoter-driven luciferase expression was efficiently regulated by administration of a BA-enriched diet. Interestingly, this vector also expressed significantly higher luciferase levels in Abcb4-/- mice, which have high levels of BAs, compared to wild type mice, or to mice receiving a vector containing the luciferase gene downstream of the constitutive alpha-1 antitrypsin promoter. In contrast, the AAV vector containing ihPr showed very low luciferase expression with no inducibility. Finally, we optimized imPr by adding three IR-1 repeats at its 5' end. This new promoter provided higher levels of luciferase than imPr both in vitro and in vivo.The imPr could represent a useful tool for gene therapy approaches in which physiological BA regulation is desired.
2019-05-16 | Bioinformatics‑based identification of key pathways and candidate genes for estrogen‑induced intrahepatic cholestasis using DNA microarray analysis
Estrogen‑induced intrahepatic cholestasis (EIC) has increased incidence during pregnancy, and within women taking oral contraception and postmenopausal hormone replacement therapy. However, the pathology underlying EIC is not well understood. The aim of the present study was to identify key pathways and candidate genes in estrogen‑induced intrahepatic cholestasis (EIC) that may be potential targets for diagnosis and treatment. A whole‑genome microarray (4x44K) analysis of a 17α‑ethinylestradiol (EE)‑induced EIC rat liver model was performed. Bioinformatics‑based methods were used to identify key pathways and candidate genes associated with EIC. The candidate genes were validated using a reverse transcription quantitative polymerase chain reaction assay. A total of 455 genes were differentially expressed (P<0.05 and fold change >2.0) following EE treatment, including 225 downregulated genes and 230 upregulated genes. Sulfotransferase family 1E member 1, cytochrome P450 family 3 subfamily A member 2, carbonic anhydrase 3, leukotriene C4 synthase and ADAM metallopeptidase domain 8 were the 5 candidate genes identified to be differentially expressed and involved in the metabolism of estrogens and bile acids and the regulation of inflammation and oxidative stress. The Analyses of Gene Ontology enrichment, Kyoto Encyclopedia of Genes and Genomes pathways and protein‑protein interaction network associated‑modules identified several key pathways involved in the homeostasis of lipids and bile acids and in AMPK, p53 and Wnt signaling. These key pathways and candidate genes may have critical roles in the pathogenesis of EIC. In addition, reversing the abnormal expression of candidate genes or restoring the dysfunction of key pathways may provide therapeutic opportunities for patients with EIC.
2018-10-24 | ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum
Abstract ATP-binding cassette subfamily B member 4 (ABCB4) is a phospholipid translocator at the canalicular membrane of the hepatocyte, which “flops” phosphatidylcholine into bile. Dysfunction of this transporter due to ABCB4 gene variants can cause liver diseases and has been called ABCB4 deficiency. Several diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3), low phospholipid-associated cholelithiasis (LPAC), a subgroup of patients developing intrahepatic cholestasis of pregnancy (ICP), drug-induced liver injury and chronic cholangiopathy with biliary fibrosis and cirrhosis were attributed to ABCB4 deficiency and characterized in the past decade. LPAC and ICP are usually caused by monoallelic variants, whereas patients affected by PFIC3 are homozygous or compound heterozygous carriers of ABCB4 variants. Treatment with ursodeoxycholic acid is often effective, but as the more severe forms of ABCB4 deficiency progress, nevertheless, new diagnostic and therapeutic approaches are warranted. Current functional classifications for ABCB4 deficiency–associated mutations can guide the development of novel genotype–based targeted pharmacotherapies for these conditions. Recently, increasing evidence from genome-wide association studies is emerging on associations of ABCB4 variants with hepatobiliary malignancies.
cell therapies
2025-11-26 | Plasmapheresis for Suspected Drug-Induced Liver Injury During Pregnancy: A Multidisciplinary Diagnostic and Therapeutic Challenge
Acute liver injury during pregnancy is rare and predominantly associated with pregnancy-related conditions including acute fatty liver of pregnancy; Hemolysis, Elevated Liver Enzymes and Low Platelets syndrome; intrahepatic cholestasis of pregnancy; and preeclampsia. Drug-induced liver injury (DILI) is a less common and often overlooked cause of acute liver injury in pregnant patients. A literature search on acute liver injury during pregnancy and therapeutic plasma exchange was conducted, revealing the most common causative factors and syndromes. A 39-year-old woman was diagnosed with acute liver injury in the 23rd week of her third pregnancy and, upon extensive differential diagnoses, a suspicion of DILI occurred after the use of methyldopa. Methyldopa, the drug of choice for the treatment of hypertensive disorders of pregnancy, has a high safety profile for the developing fetus and is well tolerated by pregnant women, yet, in susceptible individuals, a hepatotoxic effect may occur. The drug was discontinued and symptomatic treatment with ursodeoxycholic acid and prednisone was implemented with marginal effect. Upon a multidisciplinary joint consultation, plasmapheresis procedures were introduced, granting a significant improvement in the patient’s liver function and enabling the continuation of the pregnancy. Plasmapheresis treatment was safely and effectively used for the first time in the therapeutic process in a pregnant patient with DILI. Interdisciplinary cooperation of specialists with gastroenterology, nephrology, and obstetrics expertise is crucial to achieving a timely diagnosis and begin effective treatment for pregnant patients with acute liver injury.
2025-10-10 | Probiotic VSL#3 alleviates intrahepatic cholestasis of pregnancy by upregulating farnesoid X receptor-fibroblast growth factor 15 through regulation of the gut microbiota.
Intrahepatic cholestasis of pregnancy (ICP) poses significant risks to both maternal and fetal health, and treatment options remain limited. This study investigated the efficacy and underlying mechanisms of VSL#3 in alleviating ICP. Clinical fecal and blood samples were collected from 26 patients with ICP and 21 healthy pregnant women. The gut microbiota composition was analyzed using 16S rRNA sequencing. To further explore causality, we established a fecal microbiota transplantation-ICP mouse model using fecal samples from ICP patients, as well as an estrogen-induced ICP mouse model. Compared with healthy pregnant women, ICP patients exhibited a distinct gut microbiota profile, characterized by an increased abundance of Bacteroides and Alistipes. Serum FGF19 levels were significantly lower in ICP patients, showing a negative correlation with liver function markers, such as serum total bile acid (TBA), and a positive correlation with beneficial genera including Bifidobacterium, Ruminococcus, Blautia, Dorea, Eubacterium (hallii group) and Ruminococcus (torques group). VSL#3 treatment in mice alleviated ICP manifestations by improving liver histopathology, reducing TBA and alanine aminotransferase levels, increasing FGF15 concentrations, and enhancing fetal outcomes. These beneficial effects were abolished by co-administration of the FXR antagonist Z-guggulsterone, confirming the role of FXR signaling. In conclusion, VSL#3 alleviated ICP by modulating the gut microbiota to activate the FXR-FGF15 axis, thereby reducing bile acid synthesis and improving maternal and fetal outcomes.
2024-04-01 | Severe Elevated Bile Acids in Early Pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) typically presents in the second half of pregnancy. Severe ICP is associated with increased risk of stillbirth. Little is known regarding elevated bile acids in the first trimester. We present a case of severely elevated bile acids in the first trimester, resistant to conservative management, in a patient with pre-existing cholestatic liver disease and aortic valve disease requiring anticoagulation. Therapeutic plasma exchange was used. In those with pre-existing cholestatic disease, early bile acid elevation is likely distinct from ICP, and conservative strategies may not be useful. In addition, therapeutic enoxaparin appears safe in therapeutic plasma exchange.
2023-11-29 | Roseburia intestinalis relieves intrahepatic cholestasis of pregnancy through bile acid/FXR-FGF15 in rats.
Previous research has demonstrated significant differences in intestinal flora between pregnant women with intrahepatic cholestasis of pregnancy (ICP) and healthy pregnant women. The objective of our study is to identify the key bacteria involved in ICP rats and explore the underlying mechanism. We established an ICP rat model and collected rat feces for metagenomic sequencing and found that Roseburia intestinalis (R.I) is the key bacteria in ICP. Transplantation of R.I improved phenotypes associated with ICP through the bile acid/farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) signaling pathway. We used the FXR antagonist Z-Guggulsterone (Z-Gu) to verify the key role of FXR in ICP and found that Z-Gu reversed the benefits of R.I on ICP rats. Our research highlights the important role of intestinal flora in the pathogenesis of ICP and provides a novel approach for its treatment.
2023-05-18 | Principles of treatment of intrahepatic cholestasis of pregnant women
BACKGROUND:Intrahepatic cholestasis of pregnancy occupies a leading place in the structure of hepatoses associated with pregnancy. As with many other diseases that debut during gestation, all the symptoms of intrahepatic cholestasis of pregnancy disappear after delivery and have no consequences for the mother, unlike, for example, acute fatty degeneration of the liver. However, the fetal prognosis remains serious due to the high incidence of preterm birth and the toxic effect of bile components on the developing fetus, which both lead to perinatal complications. Especially fatal is the situation when intrahepatic cholestasis of pregnancy is combined with intrauterine infection, placental insufficiency, severe preeclampsia, diabetes mellitus, or other extragenital pathology. Until recently, it was believed that the only correct solution for intrahepatic cholestasis of pregnancy development was early delivery. Only in recent decades, attempts have been made to therapeutic correction of this pathology in order to prolong pregnancy to full term and reduce the frequency of perinatal complications. So far, tangible results have been achieved with the use of ursodeoxycholic acid preparations and the introduction of efferent methods of therapy into obstetric practice.
AIM:The aim of this study was to develop optimal schemes for pathogenetic therapy of intrahepatic cholestasis of pregnancy using hepatoprotectors from the ursodeoxycholic acid group, as well as ademetionine, essential phospholipids, and membrane plasmapheresis.
MATERIALS AND METHODS:This study included 150 pregnant women with intrahepatic cholestasis of pregnancy. Group I (n= 50) comprised patients who were treated only with ursodeoxycholic acid. Group II (n= 50) included individuals who were given combined drug therapy with ursodeoxycholic acid, ademetionine, and essential phospholipids. Group III (n= 50) consisted of women whose treatment included efferent therapies (membrane plasmapheresis) in combination with ursodeoxycholic acid or ademetionine preparations. All pregnant women before the start of therapy were determined the blood levels of bile acids, total and direct bilirubin, and transaminases (alanine aminotransferase, aspartate aminotransferase). Blood parameters were monitored once every seven days. All the patients were also monitored for the condition of the fetus (fetometry, dopplerometry, cardiotocography).
RESULTS:The use of ursodeoxycholic acid not combined with other hepatoprotectors (group I) was possible only in cases of increased blood levels of bile acids of not more than 40 mmol/L, preparations of ademetionine and essential phospholipids as monotherapy being ineffective. With an increase in the blood levels of bile acids of more than 40 mmol/L and transaminases by two to three or more times from the upper limit of the norm (group II), the most effective was the combined use of ursodeoxycholic acid, ademetionine and essential phospholipid preparations. The most significant decrease in the blood levels of bile acids and hepatic cytolysis parameters (transaminases) was observed when plasmapheresis was used in combination with ursodeoxycholic acid or ademetionine (group III).
CONCLUSIONS:The choice of treatment regimen depends on the level of increase in bile acids and the severity of cytolytic syndrome. With an increase in the level of bile acids to 40 mmol/L, ursodeoxycholic acid preparations can be used only. With an increase in bile acid level of more than 40 mmol/L, the complex use of the above hepatoprotectors is necessary. The most effective treatment regimen is the use of membrane plasmapheresis in combination with ursodeoxycholic acid or ademetionine.
proteins
2026-04-21 | Peptidomics Landscape of Intrahepatic Cholestasis of Pregnancy and its Molecular Mechanism Investigation.
Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that poses substantial health risks to both mother and fetus. However, its pathogenesis remains unclear. Our previous study highlighted the significance of ferroptosis in ICP. To fully elucidate the pathogenesis of ferroptosis related to ICP and identify new therapeutic strategies, we used nanoscale liquid chromatography coupled with tandem mass spectrometry analysis in an in vitro model of ICP induced by taurocholic acid to investigate the peptidomics of ICP. The peptide profile successfully revealed 27,527 peptides, of which 1,180 were related to ferroptotic differentially expressed peptides in the screened ICP. Through comprehensive bioinformatics analyses, combined with 3,783 ICP and 1,518 ferroptosis targets, we identified 20 hub genes and molecular functions, including ubiquitin protein ligase binding, which may be involved in the development of ICP. Four potential bioactive peptides were selected through in silico analysis and further verified using in vitro, molecular docking, and molecular dynamics studies. Peptides DLTGIPPAPR and PRLPEEWSQW have the potential to enhance trophoblast viability and modulate important genes, such as HSPB1, HSPA5, and SQSTM1, which could be beneficial in managing ICP by inhibiting ferroptosis. Our findings provide crucial insight into the pathophysiological mechanisms underlying ICP.
2026-01-30 | Study on the mechanism of DLK1 in placenta of intrahepatic cholestasis of pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific disorder, prominently characterized by elevated serum bile acids and adverse fetal outcomes. This study focused on the expression of Delta-like 1(DLK1) in the placenta of patients with ICP,along with the alterations in placental blood vessels and function. The bile acid - induced ICP cell model was utilized to clarify the impact of DLK1 on the function of trophoblast cells under the pathological context of ICP. Human placental tissues were subjected to immunohistochemical staining, immunofluorescence, Western blotting (WB)and qPCR. These techniques were employed to analyze the expression of DLK1 and functional status of blood vessels in the ICP placenta. An ICP cell model was established using Taurocholate acid (TCA). WB, qPCR, and reactive oxygen species (ROS) assays were conducted to detect the effects of TCA and DLK1 on trophoblast function. The effects of TCA and DLK1 on endothelial cell function were evaluated through migration and tube formation assays. The results indicated that the expression levels of DLK1, placental growth factor, and angiogenesis factor were significantly lower in the human ICP placenta. Concomitantly, the Notch1 signaling pathway was found to be inhibited. The addition of DLK1 to the ICP cell model improved the function of the cells, and the supernatant of the trophoblast cells also promoted the migration and tube formation ability of HUVECs. In the ICP placenta, the expression of DLK1 is reduced, accompanied by a decline in placental blood vessels and placental function. Exogenous addition of DLK1 can activate the Notch1 pathway, promote placental angiogenesis and mitigate oxidative damage.
2025-08-13 | Multi-omics characterization of autophagy-related molecular features in intrahepatic cholestasis of pregnancy†.
Despite the increasing body of evidence that autophagy implicate in intrahepatic cholestasis of pregnancy (ICP), we are still far from a mechanistic understanding of the autophagy in ICP pathogenesis. In this study, we performed untargeted lipidomics, scRNA-seq, and RNA-seq data to systematically demonstrate the lipid alterations, cells and gene expression closely related to autophagy in placenta. These results were also verified by tissue, cell, and animal experiments. We confirmed that autophagy played a pivotal role in ICP, autophagy-related lipids including PE (38:2e) and PE (54:5) had a good diagnostic value. Autophagy genes were mainly concentrated in villous cytotrophoblast (VCT), extravillous trophoblast (EVT), and macrophage. VCT was found increased while EVT decreased in ICP. In the subcluster analysis of VCT, VCT-EVT, the precursor cells of EVT, was significantly reduced. In the subcluster analysis of EVT, EVT2 cells with epithelial migration and regulatory functions were significantly reduced. Furthermore, autophagy gene TNFSF10 was decreased in ICP, while supplementation of soluble TNFSF10 could restore the expression of TNFSF10 in ICP cell model, which alleviated the autophagic damage and improved the invasion and migration ability of trophoblast cells. Our study established the causal linkage between autophagy and ICP, providing a potential therapeutic avenue to improve trophoblast function accounting for ICP by targeting autophagy gene TNFSF10.
2025-08-09 | Mendelian Randomization Study of Sex Hormone Binding Globulin and Its Influence on Adverse Pregnancy Outcomes.
The relationship between sex hormone-binding globulin (SHBG) levels and the risk of adverse pregnancy outcomes (APOs) remains controversial. A two-sample Mendelian randomization (MR) study was performed to clarify the causality of SHBG on the risk of APO. Significant single-nucleotide polymorphisms (SNPs) associated with SHBG levels were obtained from the genome-wide association study (GWAS) in the European population. Summary statistics of the number of spontaneous miscarriages, preeclampsia, gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy (ICP), and female infertility were utilized as the outcome. The causality was examined primarily by inverse-variance weighted (IVW), along with MR-Egger regression, weighted median estimator, and weighted mode method. Based on the IVW model, every genetically predicted standard deviation (SD) increase in SHBG levels was causally associated with 0.023 SDs decrease of the number of spontaneous miscarriages (Beta ± SE: -0.023 ± 0.010, p = 0.018), 11.3% decrease of the risk of preeclampsia (OR = 0.887, 95% CI: 0.806-0.977, p = 0.015), 17% decrease of the risk of GDM (OR = 0.830, 95% CI: 0.753-0.914, p = 0.000), 23.6% decrease of the risk of ICP (OR = 0.764, 95% CI: 0.584-0.999, p = 0.049), and 14% decrease of the risk of infertility (OR = 0.860, 95% CI: 0.777-0.951, p = 0.003). Our study indicated that the increased levels of SHBG could significantly reduce the risk of APO. SHBG may be helpful as the indicator for preconception risk assessment and pregnancy risk monitoring. These findings are limited to European and require further validation in diverse populations.
2022-08-19 | The effectiveness of small heterodimer partner and FGF 19 levels in prediction of perinatal morbidity in intrahepatic cholestasis of pregnancy.
Fibroblast growth factor 19 (FGF19) and small heterodimer partner (SHP) are molecules responsible for controlling serum bile acid levels. We designed this study for evaluating the effects of FGF 19 and SHP in intrahepatic cholestasis of pregnancy (ICP). Fifty-six pregnant women having ICP and 20 healthy pregnant women were included in the study. The patients were followed up until delivery in terms of pregnancy-related morbidity/mortality. Serum FGF 19 and SHP levels were determined by enzyme-linked immunosorbent assay (ELISA). Serum FGF 19 and SHP levels were significantly higher in the patient group compared to the control group (p: .04, p: .003, respectively). In ROC analysis, SHP level above 1995 ng/L was found effective in predicting the need for neonatal intensive care unit (ICU) follow-up with 53.8% sensitivity and 77.8% specificity. High SHP levels were correlated with perinatal morbidity, mortality and neonatal ICU hospitalisation.Impact StatementWhat is already known on this subject? Itching, elevated serum transaminase and serum total bile acid (TBA) levels are the most important clinical and biochemical findings of intrahepatic cholestasis of pregnancy (ICP). Fibroblast growth factor 19 (FGF19) and small heterodimer partner (SHP) are molecules - responsible for controlling serum bile acid levels. ICP is associated with preterm labour, asphyxia, foetal distress, stillbirth and preeclampsia.What do the results of this study add? Serum FGF 19 and SHP levels were significantly higher in the patient group compared to the control group. High SHP level was found effective in predicting the need for neonatal intensive care unit and showed a negative correlation with birth week and birth weight.What are the implications of these findings for clinical practice and/or further research? Checking SHP levels can help to predict perinatal mortality and morbidity. Treatments to be developed through the mechanism of action of FGF 19 and SHP can be promising in the treatment of ICP and other cholestatic liver diseases.
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2026-04-22 | PIP2 Accumulation in the Spongiotrophoblast Drives Trophoblast Apoptosis in Intrahepatic Cholestasis of Pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by elevated maternal bile acids and an increased risk of adverse fetal outcomes. Although placental dysfunction is a key contributor to ICP pathogenesis, the underlying mechanisms remain incompletely understood. Here, we combined a Sprague-Dawley rat model of ICP with spatial metabolomics to delineate region-specific metabolic alterations within the placenta. Multivariate analysis revealed distinct metabolic signatures between ICP and control placentas, with pronounced reprogramming in trophoblast-enriched regions. Differential metabolite and pathway analyses identified significant perturbations in glycerophospholipid metabolism, pyruvate metabolism, phospholipase D signaling, and the tricarboxylic acid cycle. Notably, phosphatidic acid (PA) was broadly elevated, whereas its downstream product phosphatidylinositol 4,5-bisphosphate (PIP2) exhibited spatially restricted accumulation in trophoblasts. Mechanistically, taurocholic acid exposure in HTR-8/SVneo cells induced upregulation of PIP5K1, leading to PIP2 accumulation and increased trophoblast apoptosis via disruption of the Bcl-2/Bax balance. Silencing of PIP5K1 restored PIP2 homeostasis and attenuated apoptosis. Importantly, these molecular alterations were recapitulated in placental tissues from ICP patients, confirming activation of the PIP5K1-PIP2 axis in vivo. Collectively, our findings identify a spatially resolved PA-PIP5K1-PIP2 lipid signaling cascade that links bile acid-induced metabolic stress to trophoblast apoptosis and placental dysfunction in ICP.
2025-09-19 | MicroRNA-940 Induces Apoptosis of HTR8-S/Vneo Cells in Intrahepatic Cholestasis of Pregnancy by Regulating RhoA.
The expression of microRNA is likely to be closely associated with intrahepatic cholestasis of pregnancy (ICP). This study aimed to investigate the potential mechanisms underlying miR-940/RhoA-induced apoptosis in HTR8-S/Vneo cells in ICP. In this study, 80 pregnant women diagnosed with ICP were recruited, with healthy pregnant women as controls. RT-qPCR was utilized to quantify the expression levels of miR-940 and RhoA. Cell proliferation was evaluated using the CCK-8 assay, while flow cytometry was employed to assess cell apoptosis. The dual-luciferase reporter assay confirmed the targeting relationship between miR-940 and RhoA. miR-940 expression was significantly elevated in the ICP group. ROC curve analysis demonstrated that miR-940 exhibited high diagnostic accuracy for ICP. Cell proliferation assays indicated that miR-940 negatively regulates cell proliferation. Apoptosis experiments revealed that low levels of miR-940 inhibited apoptosis. The dual-luciferase reporter assay confirmed that miR-940 targeted RhoA, establishing a negative correlation between them. The reversed experiment demonstrated that while the downregulation of miR-940 promoted cell proliferation and inhibited apoptosis, these effects were partially reversed when RhoA expression was suppressed. In conclusion, miR-940 played a crucial role in regulating cell proliferation and apoptosis, and it held potential as a therapeutic target for inhibiting the apoptosis of HTR8-S/Vneo cells in ICP.
2024-04-19 | Exosomes from Intrahepatic Cholestasis of Pregnancy Induce Cell Apoptosis Through the miRNA-6891-5p/YWHAE Pathway.
Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse pregnancy outcomes; however, the underlying mechanisms are not fully understood. This study aimed to determine the role of exosomal miR-6891-5p in placental trophoblast dysfunction in ICP and identify new biomarkers for ICP diagnosis. Serum samples were collected from ICP patients and healthy pregnant women, and serum exosomes were extracted and identified. Fluorescent dye labeling of exosomes and cell-verified cell phagocytosis were performed. In vitro experiments were conducted by adding taurocholic acid to simulate the ICP environment. Cell proliferation and apoptosis levels were detected using flow cytometry and the cell counting kit-8 assay. Mimics were constructed to overexpress miR-6891-5p in cells, and the binding site between miR-6891-5p and YWHAE was verified using luciferase reporter genes. miR-6891-5p expression was significantly decreased in serum exosomes of ICP patients. Co-culturing with exosomes derived from ICP patients' serum (ICP-Exos) decreased HTR-8/SVeno cell proliferation and increased apoptosis levels. miR-6891-5p upregulation in HTR-8/SVeno cells significantly increased cell viability and reduced cell apoptosis levels, as determined by the cell counting kit-8 assay and flow cytometry. A double luciferase assay confirmed that miR-6891-5p affected the expression of the downstream YWHAE protein. This study indicates that serum exosomes from ICP patients can impact the apoptosis of placental trophoblast HTR-8/SVeno cells through the miR-6891-5P/YWHAE pathway and can serve as specific molecular markers for ICP diagnosis.
2022-07-12 | Immune Dysfunction Mediated by the ceRNA Regulatory Network in Human Placenta Tissue of Intrahepatic Cholestasis Pregnancy.
Pregnancy-related intrahepatic cholestasis (ICP) is a serious complication with adverse perinatal outcomes of preterm labor, fetal distress, or stillbirth. As a result, it is important to investigate and identify the potential critical pathogenic mechanisms of ICP. First, we collected the placental tissues from the ICP with placental weight and fetal birth weight loss for the whole transcriptome sequencing. Then we analyzed the differentially expressed (DE) circRNAs (DEcircRNAs) by SRPBM, DElncRNAs by FRKM, DEmiRNAs by TPM, and DEmRNAs by TPM and RSEM. Based on differential expression of term pregnancy placental tissues from pregnancies impacted by ICP (n=7) as compared to gestational aged matched control tissues (n=5), the circ/lncRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) regulatory networks were constructed. The ceRNA regulatory networks covered 3,714 events, including 21 DEmiRNAs, 36 DEcircRNAs, 146 DElncRNAs, and 169 DEmRNAs. According to the functional analysis, ICP complications were linked to the immune system, signal transduction, endocrine system, cell growth and death, and transport and catabolism. Further evidence suggested that the expression of immune-related genes KLRD1, BRAF, and NFATC4 might have a potential ceRNA mechanism by individual lncRNA sponging miR372-3p, miR-371a-3p, miR-7851-3p, and miR-449a to control downstream the level of TNF-α, IFN-γ, and IL-10, thereby regulating the pathophysiology of ICP. Furthermore, our results were validated by the qRT-PCR, western blotting and ELISA assays. In conclusion, this study is the first to evaluate placental ceRNA networks in pregnancies affected by ICP, showing alterations in immune regulatory networks which may impact fetal and placental growth. Overall our these data suggest that the ceRNA regulatory network may refine biomarker predictions for developing novel therapeutic approaches in ICP.
2022-06-03 | Circ_0060731 mediated miR-21-5p-PDCD4/ESR1 pathway to induce apoptosis of placental trophoblasts in intrahepatic cholestasis of pregnancy.
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy complication. However, the pathogenesis of ICP is currently unclear. We analyzed the placenta samples of 10 normal and 10 ICP pregnant women. the expressions of circ0060731, miR-21-5p, and their downstream target genes PDCD4, ESR1, and apoptotic protein cleaved-caspase3 were detected in the cell model. The expression of Circ_0060731, PDCD4, ESR1, and caspase-3 was higher in the ICP placenta tissue than in the control group, and the expression of miR-21-5p was lower in the ICP group than in the control group. In HTR8/Svneo cells treated with TCA, the expression/levels of Circ_0060731, PDCD4, ESR1, and caspase-3 were significantly higher in the ICP group than in the control group, and miR-21-5p was significantly lower in the ICP group than in the control group. Lentiviral knockdown of miR-21-5p significantly increased the expressions of its downstream genes of PDCD4 and ESR1, and also increased cell apoptosis. Overexpression of miR-21-5p significantly reduced the expression of PDCD4 and ESR1 and reduced cell apoptosis. The dual-luciferase experiment showed that both PDCD4 and ERS1 were the target genes of miR-21-5p. Circ_0060731 mediated miR-21-5p-PDCD4/ESR1 pathway could induce apoptosis of placental trophoblasts in intrahepatic cholestasis of pregnancy.
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