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
671
papers
On emerging therapies
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
671 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:
671 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
2026-09-28 | Impact of elevated maternal bile acid levels on fetomaternal outcomes in intrahepatic cholestasis of pregnancy: a retrospective observational study
Background: Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver disorder associated with elevated maternal bile acids and adverse perinatal outcomes. The degree of bile acid elevation is considered a key prognostic marker. To evaluate the impact of elevated maternal bile acid levels on maternal and neonatal outcomes and to identify bile acid thresholds associated with adverse pregnancy outcomes. Methods: A retrospective study was conducted at Mediclinic Welcare Hospital, Dubai, from January 2023 to December 2024. Sixty pregnant women diagnosed with ICP were included after exclusion of incomplete records. Patients were categorized based on bile acid levels into gestational pruritus (<19 µmol/l), mild (19–39 µmol/l), moderate (40–99 µmol/l), and severe (≥100 µmol/l). Maternal and neonatal outcomes were analyzed. Results: Most patients had gestational pruritus (65%) followed by mild (26.7%), moderate (6.7%), and severe ICP (1.7%). The majority were South Asian (73.3%) and multigravida (61.7%). No significant association was found between bile acid levels and maternal complications. Term delivery occurred in 83.3% of cases. Neonatal outcomes were favorable in 71.7%, with NICU admissions (26.7%) primarily due to respiratory distress rather than bile acid severity. Ursodeoxycholic acid therapy improved bile acid levels in nearly half of the cases. Conclusions: Intrahepatic cholestasis of pregnancy was associated with favourable maternal and neonatal outcomes in this cohort when managed with close antenatal surveillance, bile acid monitoring, and individualized timing of delivery.
2026-09-06 | Temporal association between adjunctive bicyclol initiation and discordant biochemical trends in severe early-onset pregnancy-associated cholestasis: a Case Report.
Severe early-onset pregnancy-associated cholestasis with atypical features may reflect an intrahepatic cholestasis of pregnancy (ICP) component superimposed on underlying hepatobiliary disease. Evidence for bicyclol use during pregnancy is very limited. A 34-year-old pregnant woman, developed palmoplantar pruritus and severe cholestasis at 15 weeks of gestation. She had previously undergone cholecystectomy and common bile duct exploration. The working diagnosis was pregnancy-associated cholestasis with a possible ICP component superimposed on suspected chronic hepatobiliary dysfunction. Biochemical abnormalities persisted despite treatment with ursodeoxycholic acid, ademetionine, glutathione, and polyene phosphatidylcholine. Off-label bicyclol at 50 mg three times daily was added at 29 weeks and continued for approximately 5 weeks. Before bicyclol was added, alanine aminotransferase (ALT) level ranged from 724 to 1,492 U/L, and total bile acids (TBA) level ranged from 111.2 to 224.6 μmol/L. Following bicyclol initiation, ALT ranged from 137 to 464 U/L. TBA remained markedly elevated, ranging from 96.7 to 146.6 μmol/L. Total bilirubin ranged from 42.8 to 46.5 μmol/L. Overall, aminotransferase levels were lower than the pretreatment range, whereas TBA and total bilirubin remained markedly elevated. Cesarean delivery was performed at 34+1 weeks of gestation because of worsening maternal symptoms and persistent hyperbilirubinemia. Grade III meconium-stained amniotic fluid was noted during surgery. A liveborn female infant was delivered with Apgar scores of 10, 10, and 10 at 1, 5, and 10 min, respectively. No early neonatal complications were observed. At 42 days postpartum, liver tests remained mildly abnormal, which suggested persistent hepatobiliary dysfunction rather than cholestasis limited to pregnancy. A temporal association was observed between bicyclol initiation and lower aminotransferase levels. However, this temporal association should not be interpreted as evidence of causality because multiple factors, including substantial pretreatment biochemical variability, concomitant multidrug therapy, advancing gestation, and possible underlying hepatobiliary disease, may have contributed to the observed changes. This case does not establish efficacy, pregnancy prolongation, or maternal and fetal safety. Instead, it provides a hypothesis-generating observation and highlights the need for further structural and genetic evaluation and systematic studies with long-term infant follow-up.
2026-09-01 | Comparison of maternal and perinatal outcome in normal vs Intrahepatic Cholestasis of Pregnancy: A case control study
Intrahepatic Cholestasis of Pregnancy (IHCP) also known as Obstetrics Cholestasis of pregnancy is the most common pregnancy- specific liver disease. The biochemical abnormalities and symptoms resolve rapidly after delivery but it may recur in subsequent pregnancies and also with the use of hormonal contraception. IHCP consistently associated with a higher incidence of adverse pregnancy outcomes, including spontaneous and iatrogenic preterm delivery, non-reassuring foetal status, meconium staining of amniotic fluid and stillbirth. Methods: A prospective case control study was done among 57 women having IHCP and 57 women of normal pregnancy. Their LFTs and bile acid values were recorded and differentiated accordingly. Results: A total of 114 patients (57 cases and 57 controls) were analysed. All liver enzymes assessed in our study showed marked elevation among IHCP cases compared to controls, with highly significant differences (p < 0.0001). Adverse maternal outcomes like preterm labour, pre-eclampsia, postpartum haemorrhage, gestational diabetes mellitus and adverse foetal outcomes such as low APGAR score, NICU admission, foetal growth restriction, preterm birth, meconium stained liquor were more common with pregnant women who had IHCP. Interpretation & Conclusion: In this study, we concluded that women diagnosed with IHCP have more maternal and foetal complications.
2026-08-25 | Methyldopa reduces plasma bile acid concentrations in a murine model of estrogen-induced cholestasis.
Bile acids (BAs) are steroidal molecules with endocrine and exocrine functions, eliminated primarily via bile. Intrahepatic cholestasis of pregnancy (ICP) features elevated maternal BA concentrations linked to adverse perinatal outcomes. Hypertensive disorders of pregnancy, often managed with methyldopa, co-occur with BA dysregulation, yet the impact of methyldopa on BA homeostasis is unclear. We examined methyldopa in a murine model of estrogen-induced cholestasis. Female C57BL/6J mice received ethinylestradiol (10 mg/kg, s.c.) with or without methyldopa (250 mg/kg, p.o.) for 7 days. BA profiles were quantified by LC-MS across plasma, bile, liver, urine, intestine, and feces. Hepatic, ileal, and renal expression of BA-related enzymes/transporters was assessed by RT-qPCR and Western blotting. In estrogen-challenged mice, methyldopa selectively reduced total BA concentrations in plasma and liver without increasing fecal or urinary BA excretion. The lowering coincided with induction of CAR-responsive detoxification/export markers, particularly Cyp2b10 and Abcc3/Mrp3, together with partial restoration of nuclear CAR and reduced p-ERK1/2 normalized to total ERK1/2. Methyldopa also reduced hepatic free cholesterol in cholestatic mice, accompanied by reduced Hmgcr abundance and increased Acat2 expression, indicating altered cholesterol handling that may limit substrate availability for BA synthesis. In conclusion, methyldopa lowered BA plasma concentrations under estrogenic stress consistent with reduced substrate availability for BA synthesis and enhanced detoxification/export. In the context of pregnancy-related BA dysregulation, these findings suggest that methyldopa, when used for hypertensive disorders of pregnancy, does not exacerbate BA accumulation and may selectively attenuate it; this hypothesis warrants clinical evaluation.
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).
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
2026-08-19 | Plasma exchange-based artificial liver support for acute liver failure associated with early-onset intrahepatic cholestasis of pregnancy: a case report
Abstract Background Intrahepatic cholestasis of pregnancy (ICP) is typically benign, but progression to acute liver failure (ALF) is a rare, life-threatening complication. We report a case of ALF associated with early-onset ICP managed successfully with plasma exchange-based artificial liver support system (ALSS). Case presentation A 29-year-old Chinese woman (G2P1) presented with abnormal liver function at 20 weeks of gestation, characterized by markedly elevated aminotransferases but only mildly increased total bile acid (TBA, 12.4 µmol/L). Despite supportive care, she developed progressive cholestasis, hyperbilirubinemia, coagulopathy, and mild encephalopathy. Pregnancy was terminated at 23 weeks due to disease progression. Post-termination, TBA surged to 360.9 µmol/L, indicating persistent severe cholestasis. Given the poor response to conventional therapy, sequential ALSS combining Double Plasma Molecular Adsorption System (DPMAS) and plasma exchange was initiated. The patient exhibited rapid biochemical improvement and recovered fully without liver transplantation. Conclusions This case illustrates a rare clinical presentation of acute liver failure associated with early-onset intrahepatic cholestasis of pregnancy in the setting of multiple potential contributing factors. Plasma exchange-based artificial liver support may provide temporary extracorporeal support for selected patients with progressive pregnancy-associated hepatic dysfunction. Further studies are required to clarify the optimal timing, indications, and clinical benefits of this therapy.
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.
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
2026-09-28 | Impact of elevated maternal bile acid levels on fetomaternal outcomes in intrahepatic cholestasis of pregnancy: a retrospective observational study
Background: Intrahepatic cholestasis of pregnancy (ICP) is a reversible liver disorder associated with elevated maternal bile acids and adverse perinatal outcomes. The degree of bile acid elevation is considered a key prognostic marker. To evaluate the impact of elevated maternal bile acid levels on maternal and neonatal outcomes and to identify bile acid thresholds associated with adverse pregnancy outcomes. Methods: A retrospective study was conducted at Mediclinic Welcare Hospital, Dubai, from January 2023 to December 2024. Sixty pregnant women diagnosed with ICP were included after exclusion of incomplete records. Patients were categorized based on bile acid levels into gestational pruritus (<19 µmol/l), mild (19–39 µmol/l), moderate (40–99 µmol/l), and severe (≥100 µmol/l). Maternal and neonatal outcomes were analyzed. Results: Most patients had gestational pruritus (65%) followed by mild (26.7%), moderate (6.7%), and severe ICP (1.7%). The majority were South Asian (73.3%) and multigravida (61.7%). No significant association was found between bile acid levels and maternal complications. Term delivery occurred in 83.3% of cases. Neonatal outcomes were favorable in 71.7%, with NICU admissions (26.7%) primarily due to respiratory distress rather than bile acid severity. Ursodeoxycholic acid therapy improved bile acid levels in nearly half of the cases. Conclusions: Intrahepatic cholestasis of pregnancy was associated with favourable maternal and neonatal outcomes in this cohort when managed with close antenatal surveillance, bile acid monitoring, and individualized timing of delivery.
2026-09-06 | Temporal association between adjunctive bicyclol initiation and discordant biochemical trends in severe early-onset pregnancy-associated cholestasis: a Case Report.
Severe early-onset pregnancy-associated cholestasis with atypical features may reflect an intrahepatic cholestasis of pregnancy (ICP) component superimposed on underlying hepatobiliary disease. Evidence for bicyclol use during pregnancy is very limited. A 34-year-old pregnant woman, developed palmoplantar pruritus and severe cholestasis at 15 weeks of gestation. She had previously undergone cholecystectomy and common bile duct exploration. The working diagnosis was pregnancy-associated cholestasis with a possible ICP component superimposed on suspected chronic hepatobiliary dysfunction. Biochemical abnormalities persisted despite treatment with ursodeoxycholic acid, ademetionine, glutathione, and polyene phosphatidylcholine. Off-label bicyclol at 50 mg three times daily was added at 29 weeks and continued for approximately 5 weeks. Before bicyclol was added, alanine aminotransferase (ALT) level ranged from 724 to 1,492 U/L, and total bile acids (TBA) level ranged from 111.2 to 224.6 μmol/L. Following bicyclol initiation, ALT ranged from 137 to 464 U/L. TBA remained markedly elevated, ranging from 96.7 to 146.6 μmol/L. Total bilirubin ranged from 42.8 to 46.5 μmol/L. Overall, aminotransferase levels were lower than the pretreatment range, whereas TBA and total bilirubin remained markedly elevated. Cesarean delivery was performed at 34+1 weeks of gestation because of worsening maternal symptoms and persistent hyperbilirubinemia. Grade III meconium-stained amniotic fluid was noted during surgery. A liveborn female infant was delivered with Apgar scores of 10, 10, and 10 at 1, 5, and 10 min, respectively. No early neonatal complications were observed. At 42 days postpartum, liver tests remained mildly abnormal, which suggested persistent hepatobiliary dysfunction rather than cholestasis limited to pregnancy. A temporal association was observed between bicyclol initiation and lower aminotransferase levels. However, this temporal association should not be interpreted as evidence of causality because multiple factors, including substantial pretreatment biochemical variability, concomitant multidrug therapy, advancing gestation, and possible underlying hepatobiliary disease, may have contributed to the observed changes. This case does not establish efficacy, pregnancy prolongation, or maternal and fetal safety. Instead, it provides a hypothesis-generating observation and highlights the need for further structural and genetic evaluation and systematic studies with long-term infant follow-up.
2026-09-01 | Comparison of maternal and perinatal outcome in normal vs Intrahepatic Cholestasis of Pregnancy: A case control study
Intrahepatic Cholestasis of Pregnancy (IHCP) also known as Obstetrics Cholestasis of pregnancy is the most common pregnancy- specific liver disease. The biochemical abnormalities and symptoms resolve rapidly after delivery but it may recur in subsequent pregnancies and also with the use of hormonal contraception. IHCP consistently associated with a higher incidence of adverse pregnancy outcomes, including spontaneous and iatrogenic preterm delivery, non-reassuring foetal status, meconium staining of amniotic fluid and stillbirth. Methods: A prospective case control study was done among 57 women having IHCP and 57 women of normal pregnancy. Their LFTs and bile acid values were recorded and differentiated accordingly. Results: A total of 114 patients (57 cases and 57 controls) were analysed. All liver enzymes assessed in our study showed marked elevation among IHCP cases compared to controls, with highly significant differences (p < 0.0001). Adverse maternal outcomes like preterm labour, pre-eclampsia, postpartum haemorrhage, gestational diabetes mellitus and adverse foetal outcomes such as low APGAR score, NICU admission, foetal growth restriction, preterm birth, meconium stained liquor were more common with pregnant women who had IHCP. Interpretation & Conclusion: In this study, we concluded that women diagnosed with IHCP have more maternal and foetal complications.
2026-08-25 | Methyldopa reduces plasma bile acid concentrations in a murine model of estrogen-induced cholestasis.
Bile acids (BAs) are steroidal molecules with endocrine and exocrine functions, eliminated primarily via bile. Intrahepatic cholestasis of pregnancy (ICP) features elevated maternal BA concentrations linked to adverse perinatal outcomes. Hypertensive disorders of pregnancy, often managed with methyldopa, co-occur with BA dysregulation, yet the impact of methyldopa on BA homeostasis is unclear. We examined methyldopa in a murine model of estrogen-induced cholestasis. Female C57BL/6J mice received ethinylestradiol (10 mg/kg, s.c.) with or without methyldopa (250 mg/kg, p.o.) for 7 days. BA profiles were quantified by LC-MS across plasma, bile, liver, urine, intestine, and feces. Hepatic, ileal, and renal expression of BA-related enzymes/transporters was assessed by RT-qPCR and Western blotting. In estrogen-challenged mice, methyldopa selectively reduced total BA concentrations in plasma and liver without increasing fecal or urinary BA excretion. The lowering coincided with induction of CAR-responsive detoxification/export markers, particularly Cyp2b10 and Abcc3/Mrp3, together with partial restoration of nuclear CAR and reduced p-ERK1/2 normalized to total ERK1/2. Methyldopa also reduced hepatic free cholesterol in cholestatic mice, accompanied by reduced Hmgcr abundance and increased Acat2 expression, indicating altered cholesterol handling that may limit substrate availability for BA synthesis. In conclusion, methyldopa lowered BA plasma concentrations under estrogenic stress consistent with reduced substrate availability for BA synthesis and enhanced detoxification/export. In the context of pregnancy-related BA dysregulation, these findings suggest that methyldopa, when used for hypertensive disorders of pregnancy, does not exacerbate BA accumulation and may selectively attenuate it; this hypothesis warrants clinical evaluation.
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).
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
2026-08-19 | Plasma exchange-based artificial liver support for acute liver failure associated with early-onset intrahepatic cholestasis of pregnancy: a case report
Abstract Background Intrahepatic cholestasis of pregnancy (ICP) is typically benign, but progression to acute liver failure (ALF) is a rare, life-threatening complication. We report a case of ALF associated with early-onset ICP managed successfully with plasma exchange-based artificial liver support system (ALSS). Case presentation A 29-year-old Chinese woman (G2P1) presented with abnormal liver function at 20 weeks of gestation, characterized by markedly elevated aminotransferases but only mildly increased total bile acid (TBA, 12.4 µmol/L). Despite supportive care, she developed progressive cholestasis, hyperbilirubinemia, coagulopathy, and mild encephalopathy. Pregnancy was terminated at 23 weeks due to disease progression. Post-termination, TBA surged to 360.9 µmol/L, indicating persistent severe cholestasis. Given the poor response to conventional therapy, sequential ALSS combining Double Plasma Molecular Adsorption System (DPMAS) and plasma exchange was initiated. The patient exhibited rapid biochemical improvement and recovered fully without liver transplantation. Conclusions This case illustrates a rare clinical presentation of acute liver failure associated with early-onset intrahepatic cholestasis of pregnancy in the setting of multiple potential contributing factors. Plasma exchange-based artificial liver support may provide temporary extracorporeal support for selected patients with progressive pregnancy-associated hepatic dysfunction. Further studies are required to clarify the optimal timing, indications, and clinical benefits of this therapy.
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.
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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