RARE DISEASE
Heme oxygenase-1 deficiency
Heme oxygenase-1 deficiency
Heme oxygenase-1 deficiency
Synonyms: HO-1 deficiency
Synonyms: HO-1 deficiency
Synonyms: HO-1 deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Overview:
Heme oxygenase-1 (HO-1) deficiency is a rare autosomal recessive disorder caused by HMOX1 mutations, leading to defective heme degradation and systemic oxidative stress. It manifests with severe intravascular hemolysis, congenital asplenia, progressive endothelial injury, nephropathy, and uncontrolled inflammation. Patients often develop microcytic anemia, coagulation abnormalities, and multiorgan failure, with high mortality due to complications like intracranial hemorrhage or sepsis [1][6][11][20].
Burden
High morbidity: End-stage renal disease, vascular damage, and recurrent infections dominate clinical course [1][9][11].
Mortality: Median survival <5 years post-symptom onset; fatal complications include intracranial hemorrhage/sepsis [1][6][20].
Psychosocial impact: Severe disability and care demands due to treatment-refractory systemic inflammation [1][11].
Therapies
Supportive care: Transfusions for anemia, anticoagulation for thrombosis, infection prophylaxis (asplenia) [11][20].
Experimental approaches: HO-1 inducers (e.g., hemin) and antioxidant therapies (limited efficacy) [5][13][20].
Hematopoietic stem cell transplantation explored in preclinical models; no reported human success [12][20].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
453 drug discovery papers about Heme oxygenase-1 deficiency. Recent publications:
453 drug discovery papers about Heme oxygenase-1 deficiency. Recent publications:
categories:
Small molecules
cell therapies
2026-02-10 | STING synergizes with TOX suppressing HO-1 expression to trigger ferroptosis in tumor-infiltrating CD8+ T cell and immunotherapy resistance.
CD8+ T cell abundance within the tumor microenvironment is a critical determinant of immunotherapy efficacy. Here we show that CD8⁺ T cells lacking STING or TOX display markedly improved antitumor activity, with enhanced tumor infiltration and elevated IFN-γ and granzyme B production. These STING or TOX deficient cells exhibit a stem-like transcriptional state and resist ferroptosis by suppressing lipid peroxidation pathways while promoting mitochondrial biogenesis. Mechanistically, STING and TOX form a positive regulatory loop that represses HO-1 expression, leading to iron accumulation, mitochondrial oxidative stress, and ferroptosis in tumor-infiltrating CD8⁺ T cells. We further identify lactate as a microenvironmental trigger of STING-TOX-HO-1-mediated CD8+ T-cell ferroptosis. In mouse tumor models, engineered STING/TOX-deficient CD8⁺ T cells synergize with immune checkpoint blockade, chemotherapy, or STING agonist to enhance tumor control. These findings reveal a central pathway governing CD8⁺ T-cell ferroptosis in tumors and suggest therapeutic strategies to overcome immunotherapy resistance.
2024-11-18 | Fascia-Derived Stem Cells Enhance Fat Graft Retention by Promoting Vascularization through the HMOX1-HIF-1α Pathway
Background: Adipose tissue is a widely used autologous soft tissue filler in plastic surgery, particularly for volumetric restoration in cases of soft tissue deficiency. However, effectively controlling the retention rate of transplanted fat remains a major challenge. Therefore, this study aims to explore strategies to enhance fat graft retention. We isolated fascia-derived stem cells (FDSCs) from human superficial fascia and compared their gene expression profiles with those of adipose-derived stem cells (ADSCs). Through bioinformatics analysis and functional experiments, we identified significant differences in the angiogenic potential of the two cell types. Based on sequencing results, we further investigated the roles of hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 (HMOX1). This study highlights the critical potential of FDSCs in improving fat graft retention and promoting angiogenesis, offering new strategies for enhancing graft survival and optimizing tissue regeneration therapies. Methods: We isolated fascia-derived stem cells (FDSCs) from human superficial fascia and compared them with adipose-derived stem cells (ADSCs). RNA sequencing was performed to analyze gene expression profiles, followed by bioinformatics analysis to identify differences in angiogenic potential. Functional experiments were conducted to investigate the roles of HIF-1α and HMOX1 in angiogenesis. Results: RNA sequencing revealed significant gene expression differences related to angiogenesis in FDSCs. The expression levels of HMOX1, HIF-1α, and VEGFa were significantly higher in FDSCs than in ADSCs, and HMOX1 positively regulated the expression of HIF-1α and VEGFa. In vitro experiments demonstrated that FDSCs promoted angiogenesis more effectively than ADSCs. In vivo co-transplantation experiments further confirmed that FDSCs improved fat graft retention and vascularization. Conclusions: We demonstrated that FDSCs can more effectively promote vascularization both in vitro and in vivo, and significantly improve graft retention, indicating their broad potential for future applications in tissue repair and regeneration.
2022-03-02 | Exosomes derived from mesenchyml stem cells ameliorate oxygen-glucose deprivation/reoxygenation-induced neuronal injury via transferring MicroRNA-194 and targeting Bach1.
The neuroprotective function of miR-194 on neurovascular endothelial cell injury is perceived as a novel method for clinical therapy. So are exosomes (EXs), being attractive in neurofunctional recovery. However, whether EXs derived from mesenchymal stromal cells (MSCs) perform the same efficacy by transferring miR-194 and the underlying mechanism remain vague. This study rooted in oxygen-glucose deprivation/reoxygenation (OGD/R) model. MSCs were isolated by gradient centrifugation and identified by flow cytometry. EXs were obtained through ultracentrifugation, whereas protein levels of specific markers (CD63, TGS101), together with Bach1, Nrf2 and HO-1 were measured by western blot. The relative mRNA expressions of Bach1, NOX1, AGSL4, GPX4 and miR-194 were measured by RT-qPCR assays. Cell viability was measured by cell counting kit-8, and cell migration was detected by wound healing assay. The interaction between miR-194 and Bach1 was predicted by starBase and confirmed by dual luciferase reporter assay. OGD/R dampened cell viability and miR-194 expression. Bach1 could bind with miR-194. miR-194 mimic attenuated the effect of OGD/R on cell viability and protein levels of Nrf2, HO-1 and Bach1, whereas Bach1 overexpression reversed the effect of miR-194 mimics. MSC-EXs could merge with HBMECs. Based on this, MSC-EXs loaded with miR-194 downregulated Bach1 protein level and iron content and the mRNA expressions of NOX1 and ACSL4, yet upregulated miR-194 and GPX4 expressions and Nrf2/HO-1 protein level in OGD/R-injured cells, whereas those carrying ShmiR-194 had the opposite effects. Our study suggested MSC-EXs loaded with miR-194 attenuated OGD/R-induced injury via targeting Bach1, providing a new therapeutic strategy for cerebral injuries.
2019-12-29 | Heme oxygenase‐1 deficiency triggers exhaustion of hematopoietic stem cells
While intrinsic changes in aging hematopoietic stem cells (HSCs) are well characterized, it remains unclear how extrinsic factors affect HSC aging. Here, we demonstrate that cells in the niche-endothelial cells (ECs) and CXCL12-abundant reticular cells (CARs)-highly express the heme-degrading enzyme, heme oxygenase 1 (HO-1), but then decrease its expression with age. HO-1-deficient animals (HO-1-/- ) have altered numbers of ECs and CARs that produce less hematopoietic factors. HSCs co-cultured in vitro with HO-1-/- mesenchymal stromal cells expand, but have altered kinetic of growth and differentiation of derived colonies. HSCs from young HO-1-/- animals have reduced quiescence and regenerative potential. Young HO-1-/- HSCs exhibit features of premature exhaustion on the transcriptional and functional level. HO-1+/+ HSCs transplanted into HO-1-/- recipients exhaust their regenerative potential early and do not reconstitute secondary recipients. In turn, transplantation of HO-1-/- HSCs to the HO-1+/+ recipients recovers the regenerative potential of HO-1-/- HSCs and reverses their transcriptional alterations. Thus, HSC-extrinsic activity of HO-1 prevents HSCs from premature exhaustion and may restore the function of aged HSCs.
2019-09-04 | Infused wild-type macrophages reside and self-renew in the liver to rescue the hemolysis and anemia of Hmox1-deficient mice.
Heme oxygenase 1 (HMOX1), the inducible enzyme that catabolizes the degradation of heme into biliverdin, iron, and carbon monoxide, plays an essential role in the clearance of senescent and damaged red blood cells, systemic iron homeostasis, erythropoiesis, vascular hemostasis, and oxidative and inflammatory stress responses. In humans, HMOX1 deficiency causes a rare and lethal disease, characterized by severe anemia, intravascular hemolysis, as well as vascular and tissue damage. Hmox1 knockout (KO) mice recapitulated the phenotypes of HMOX1-deficiency patients and could be rescued by bone marrow (BM) transplantation that engrafted donor's hematopoietic stem cells into the recipient animals after myeloablation. To find better therapy and elucidate the contribution of macrophages to the pathogenesis of HMOX1-deficiency disease, we infused wild-type (WT) macrophages into Hmox1 KO mice. Results showed that WT macrophages engrafted and proliferated in the livers of Hmox1 KO mice, which corrected the microcytic anemia, rescued the intravascular hemolysis, restored iron homeostasis, eliminated kidney iron overload and tissue damage, and provided long-term protection. These results showed that a single macrophage infusion delivered a long-term curative effect in Hmox1 KO mice, obviating the need for BM transplantation, and suggested that the HMOX1 disease stems mainly from the loss of viable reticuloendothelial macrophages. Our work provides new insights into the etiology of HMOX1 deficiency and demonstrates the potential of infusion of WT macrophages to prevent disease in patients with HMOX1 deficiency and potentially other macrophage-related diseases.
small molecules
2026-05-15 | Heme Metabolism-Derived Carbon Monoxide Regulates Skeletal Muscle Function.
Heme oxygenases, HO-1 (Hmox1) and HO-2 (Hmox2), regulate skeletal muscle homeostasis by degrading heme and generating carbon monoxide (CO), a bioactive signalling molecule. Although HO-1 is known to influence muscle fibre composition and mitochondrial function, the role of HO-2 in activity-dependent neuromuscular plasticity remains poorly understood. This study aimed to define the distinct contributions of each isoform and test whether CO could restore muscle function in HO-deficient states. We generated Hmox1/2 double-knockout mice (Hmox1/2-/-) and compared their skeletal muscle phenotype with that of single HO-1 or HO-2 knockouts and wild-type (WT) controls under sedentary and exercised conditions. We evaluated endurance capacity using treadmill running (n = 8-12 per group), assessed fibre-type distribution and neuromuscular junction (NMJ) morphology via immunohistochemistry and measured mitochondrial function using high-resolution respirometry. Primary neuronal cultures were analysed using multielectrode array recordings to assess firing dynamics. Inhaled CO was administered to test its capacity to rescue muscle phenotype and performance. HO-1 deficiency led to a significant reduction in oxidative fibres (Type I and IIa), decreased mitochondrial respiratory capacity (reduced by ~30%, p < 0.01) and diminished treadmill endurance (-40% running time vs. WT, p < 0.001). Hmox2 deficiency was associated with NMJ remodelling, increased acetylcholine receptor expression, reduced Sox2 transcription and heightened burst firing. The double deletion of HO-1/HO-2 produced an additive phenotype characterized by severe mitochondrial dysfunction, increased glycolytic fibre content and NMJ remodelling. We identify CO, a by-product of HO-1, as a crucial modulator of skeletal muscle adaptation, capable of compensating for HO deficiency. Treatment with CO in Hmox1/2-/- mice restored fibre-type distribution toward oxidative fibres (increased by 25%, p < 0.01), improved mitochondrial respiratory parameters and doubled endurance performance (p < 0.001). CO also normalized mitochondrial protein expression and modulated key metabolic pathways, including nucleotide metabolism, the TCA cycle and redox balance. HO-1 and HO-2 have distinct roles in regulating muscle phenotype and metabolic adaptation. HO-1 modulates mitochondrial content and muscle plasticity, whereas Hmox2 regulates, in part, activity-dependent neuromuscular plasticity and responsiveness to exercise. Exogenous CO effectively restores mitochondrial and functional deficits in HO-deficient muscle, mimicking endurance exercise adaptations. These findings support the therapeutic potential of CO in conditions of muscle disuse, aging or disease where exercise is limited or not feasible.
2025-12-18 | Epithelial HO-1 regulates iron availability and promotes colonic tumorigenesis in a context-dependent manner.
Induction of heme oxygenase-1 (HO-1/Hmox1) is broadly considered cytoprotective, but the role of colonic epithelial HO-1 in colitis-associated tumorigenesis is poorly defined. HO-1 catabolizes heme, releasing ferrous iron, a key driver of oxidative stress and lipid peroxidation. We observed that colonic epithelial HO-1 was induced during colitis and tumorigenesis. We also found that HO-1 was upregulated in ferroptosis-inducing conditions in murine and human colonic epithelial organoids and correlated with lipid peroxidation and ferroptosis markers in colonic tumors. In colonic epithelial organoids exposed to heme, deletion of Hmox1 amplified a compensatory oxidative stress and detoxification transcriptional program, likely reflecting unresolved oxidative and nonoxidative toxicity from heme. In vivo, epithelial HO-1-deficient mice developed significantly fewer and smaller tumors compared with littermate controls in a colitis-associated tumorigenesis model, despite similar inflammatory injury. Tumors from KO mice exhibited reduced iron levels, decreased lipid peroxidation, lower oxidative DNA damage, and decreased proliferation. Single-cell RNA sequencing of tumor epithelial cells revealed a shift from a proliferative to a stress-adaptive program with loss of HO-1. These findings identify epithelial HO-1 as a context-dependent regulator of tumorigenesis: it is protective against acute heme toxicity but promotes iron-dependent oxidative damage and proliferation in the setting of chronic inflammation.
2025-11-11 | The neonicotinoid Imidacloprid provokes Ferritinophagy/Ferroptosis Axis disruption in rats' liver: The attenuation impact of Berberine chloride-loaded nano-liposomes.
Imidacloprid (IMI) is a widely applied insecticide, with evidence linking chronic exposure to toxic effects, particularly hepatotoxicity. Recently, ferroptosis has been nominated as a new contributor to hepatotoxicity-related cell death. This study was designed to investigate whether ferroptosis and ferritinophagy are involved in IMI-induced liver injury and to explore the potential protective effect of berberine chloride-PEGylated lipid nanoparticles (BC-PL). Berberine is a well-known alkaloid with documented hepatoprotective activity. Accordingly, adult male rats in six groups were administered two doses of IMI (22.5 and 45 mg/kg), with or without 10 mg/kg of BC-PL daily for 30 days. Liver enzymes, hepatic ferrous (Fe2+) levels, markers of oxidative stress, inflammation, ferritinophagy, and ferroptosis, as well as morphological changes, were analyzed. IMI significantly elevated liver enzymes, hepatic Fe2+, oxidative stress, and inflammatory markers. It also adversely affected the expression of ferritinophagy and ferroptosis markers, upregulating nuclear receptor coactivator 4 (NCOA4), ferritin heavy chain (FTH-1), transferrin receptor 1 (TFR1), and Keap1, while downregulating glutathione peroxidase (GPx), solute carrier family 7 member 11 (SLC7A11), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). IMI-induced hepatotoxicity was further confirmed by light and electron microscopy, and hepatic injury was directly associated with IMI dosage. Administration of BC-PL mitigated IMI-induced liver damage, as evidenced by improvements in biochemical and histopathological changes. This study thus sheds light on the possible role of the ferritinophagy/ferroptosis axis in IMI-induced hepatotoxicity, and that the inhibition of ferritinophagy contributes to the efficacy of BC-PL as a nano-formulated hepatoprotective system.
2025-10-27 | Iron Deficiency Aggravates Hepatic Inflammation via Endoplasmic Reticulum Stress-Driven NF-κB Pathway Activation in Suckling Piglets
Iron deficiency (ID) imposes a significant health burden on infants and suckling piglets, yet its impact on hepatic inflammatory injury remains poorly defined. This study combined in vivo and in vitro models to investigate the underlying mechanisms. In piglets, iron deficiency triggered hepatic oxidative stress by inducing a redox imbalance and suppressing the core Nrf2/HO-1 antioxidant signaling pathway. Histopathological examination revealed structural abnormalities in ID piglet livers, including disorganized hepatic cords, cytoplasmic vacuolation, hydropic degeneration, and mononuclear inflammatory cell infiltration. Transmission electron microscopy further showed shrunk nuclear envelopes, reduced numbers of rough endoplasmic reticulum (RER), and dilated RER cisternae in hepatocytes from ID piglets. Mechanistically, ID activated endoplasmic reticulum stress (ERS) and the PERK/IRE1α branches of the unfolded protein response. RNA-seq transcriptomic analysis demonstrated significant dysregulation of immune-related pathways, accompanied by elevated pro-inflammatory cytokines (e.g.,interleukin-1 beta, IL-1β, tumor necrosis factor-alpha, TNF-α) and decreased anti-inflammatory cytokines (e.g., interleukin 4, IL-4, interleukin-10, IL-10). Central to this inflammatory response was the activation of the TLR4/NF-κB pathway, evidenced by upregulation of MyD88 and increased phosphorylation of IκBα and NF-κB p65. In vitro, deferoxamine (DFO)-induced ID in hepatocytes consistently recapitulated the key features of this phenotype, including the activation of ERS/ UPR and the TLR4/NF-κB signaling pathway. Critically, pharmacological inhibition of ERS by 4-phenylbutyrate (4-PBA) attenuated DFO-induced NF-κB activation and restored pro-/anti-inflammatory cytokine balance. In conclusion, these findings demonstrate that ID exacerbates hepatic inflammation through ERS-mediated activation of NF-κB pathway, providing novel mechanistic insights into liver injury associated with ID.
2025-10-18 | Med20 regulates myelination in the peripheral nervous system by modulating ferroptosis of Schwann cells.
Myelin sheath is essential for the maintenance of neural system functions. The mediator complex (MED) is associated with neurodegenerative diseases. Mutation of the MED subunit Med20 leads to abnormal brain development, but whether Med20 modulates myelination remains unknown. In this study, we report that Med20 is an important modulator of myelination in the peripheral nervous system. Loss of Med20 in Schwann cells (SCs) induces ferroptosis, thus impairing myelination. The functions of Med20 in SCs are mediated by its downstream target DDB1. DDB1 controls SC ferroptosis by regulating Hmox1 through a "DDB1-UHRF1-BACH1-Hmox1" transcription regulation axis and its direct interaction and subsequent simultaneous ubiquitination of the HO-1 protein. HO-1 inhibitor ZnPP or ferroptosis inhibitor Fer-1 is sufficient and efficient for antagonizing ferroptosis in SCs and restoring myelination in Med20-deficient mice. The results of our study reveal that Med20 is an important regulator in the network that controls myelination in the peripheral nervous system.
gene therapies
2025-05-03 | The NRF2/HO- 1 Pathway: a Potential Regulatory Factor in Fluoride-Induced Colonic Injury under Estrogen Deficiency.
Our previous studies have demonstrated that fluoride (F) overexposure is a risk factor for colonic microenvironment, yet its underlying mechanisms and the influencing factors remain poorly understood. Here, a rat model of F exposure (0, 25, 50, 100 mg/L in drinking water) combined with ovariectomy (OVX)-induced estrogen deficiency was established to investigate the roles of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in F-induced colonic damage under the state of estrogen deficiency. Result showed that F exposure significantly reduced occludin and claudin-1 expression, further resulting in the colon's morphology impairment. Concurrently, F suppressed epithelial proliferation, decreased goblet cell numbers, and diminished short-chain fatty acid (SCFA) production. OVX-induced estrogen deficiency exacerbated F-induced colonic barrier damage and SCFA decreased. Mechanistically, estrogen deficiency aggravated F intestinal toxicity by further inhibiting the protein expression of Nrf2 and HO-1 and upregulating Keap1 protein expression, following downregulated Bcl-2 mRNA levels and upregulated Bax and caspase-3 mRNA levels, and promoting colonic epithelial cell apoptosis. These findings identify that Nrf2/HO-1 key protein disorders are involved in F-induced colonic barrier injury, and estrogen deficiency further aggravated F intestinal toxicity.
2019-07-29 | Deletion of HO-1 blocks development of B lymphocytes in mice
B lymphocytes, a key cluster of cells composing the immune system, can protect against abnormal biological factors. Heme oxygenase-1 (HO-1) plays important roles in cell proliferation and immune regulation, but its effects on the development and growth of B lymphocytes are still unknown. Herein, the count of B lymphocytes in HO-1 gene knockout (HO-1+/−) mice was significantly lower than that of the HO-1 gene wild-type (HO-1WT) mice. Meanwhile, the cell count of HO-1+/− mice did not recover after irradiation for one week, due to the G0/G1 phase arrest of Pro-B cells and the augmented apoptosis of Pre-B cells. Up-regulation of HO-1 by lentivirus attenuated the Pro-B cell cycle arrest and Pre-B cell apoptosis. To understand the molecular mechanism by which HO-1 knockout blocked B lymphocyte development, protein-to-protein interaction network and Western blot were used. The PI3K/AKT signaling pathway mediated the regulatory effects of HO-1 on B lymphocytes. In conclusion, HO-1 is a crucial transcriptional repressor for B cell development.
2016-07-19 | Proximal tubule-targeted heme oxygenase-1 in cisplatin-induced acute kidney injury.
Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that catalyzes the breakdown of heme to biliverdin, carbon monoxide, and iron. The beneficial effects of HO-1 expression are not merely due to degradation of the pro-oxidant heme but are also credited to the by-products that have potent, protective effects, including antioxidant, anti-inflammatory, and prosurvival properties. This is well reflected in the preclinical animal models of injury in both renal and nonrenal settings. However, excessive accumulation of the by-products can be deleterious and lead to mitochondrial toxicity and oxidative stress. Therefore, use of the HO system in alleviating injury merits a targeted approach. Based on the higher susceptibility of the proximal tubule segment of the nephron to injury, we generated transgenic mice using cre-lox technology to enable manipulation of HO-1 (deletion or overexpression) in a cell-specific manner. We demonstrate the validity and feasibility of these mice by breeding them with proximal tubule-specific Cre transgenic mice. Similar to previous reports using chemical modulators and global transgenic mice, we demonstrate that whereas deletion of HO-1, specifically in the proximal tubules, aggravates structural and functional damage during cisplatin nephrotoxicity, selective overexpression of HO-1 in proximal tubules is protective. At the cellular level, cleaved caspase-3 expression, a marker of apoptosis, and p38 signaling were modulated by HO-1. Use of these transgenic mice will aid in the evaluation of the effects of cell-specific HO-1 expression in response to injury and assist in the generation of targeted approaches that will enhance recovery with reduced, unwarranted adverse effects.
2016-02-24 | Heme oxygenase-1 regulates mitochondrial quality control in the heart
The cardioprotective inducible enzyme heme oxygenase-1 (HO-1) degrades prooxidant heme into equimolar quantities of carbon monoxide, biliverdin, and iron. We hypothesized that HO-1 mediates cardiac protection, at least in part, by regulating mitochondrial quality control. We treated WT and HO-1 transgenic mice with the known mitochondrial toxin, doxorubicin (DOX). Relative to WT mice, mice globally overexpressing human HO-1 were protected from DOX-induced dilated cardiomyopathy, cardiac cytoarchitectural derangement, and infiltration of CD11b+ mononuclear phagocytes. Cardiac-specific overexpression of HO-1 ameliorated DOX-mediated dilation of the sarcoplasmic reticulum as well as mitochondrial disorganization in the form of mitochondrial fragmentation and increased numbers of damaged mitochondria in autophagic vacuoles. HO-1 overexpression promotes mitochondrial biogenesis by upregulating protein expression of NRF1, PGC1α, and TFAM, which was inhibited in WT animals treated with DOX. Concomitantly, HO-1 overexpression inhibited the upregulation of the mitochondrial fission mediator Fis1 and resulted in increased expression of the fusion mediators, Mfn1 and Mfn2. It also prevented dynamic changes in the levels of key mediators of the mitophagy pathway, PINK1 and parkin. Therefore, these findings suggest that HO-1 has a novel role in protecting the heart from oxidative injury by regulating mitochondrial quality control.
2015-12-16 | A new model of an arteriovenous fistula in chronic kidney disease in the mouse: beneficial effects of upregulated heme oxygenase-1
The arteriovenous fistula (AVF) is the preferred hemodialysis vascular access, but it is complicated by high failure rates and attendant morbidity. This study provides the first description of a murine AVF model that recapitulates two salient features of hemodialysis AVFs, namely, anastomosis of end-vein to side-artery to create the AVF and the presence of chronic kidney disease (CKD). CKD reduced AVF blood flow, observed as early as 3 days after AVF creation, and increased neointimal hyperplasia, venous wall thickness, thrombus formation, and vasculopathic gene expression in the AVF. These adverse effects of CKD could not be ascribed to preexisting alterations in blood pressure or vascular reactivity in this CKD model. In addition to vasculopathic genes, CKD induced potentially vasoprotective genes in the AVF such as heme oxygenase-1 (HO-1) and HO-2. To determine whether prior HO-1 upregulation may protect in this model, we upregulated HO-1 by adeno-associated viral gene delivery, achieving marked venous induction of the HO-1 protein and HO activity. Such HO-1 upregulation improved AVF blood flow and decreased venous wall thickness in the AVF. Finally, we demonstrate that the administration of carbon monoxide, a product of HO, acutely increased AVF blood flow. This study thus demonstrates: 1) the feasibility of a clinically relevant murine AVF model created in the presence of CKD and involving an end-vein to side-artery anastomosis; 2) the exacerbatory effect of CKD on clinically relevant features of this model; and 3) the beneficial effects in this model conferred by HO-1 upregulation by adeno-associated viral gene delivery.
proteins
2024-09-30 | Peripheral human red blood cell development in human immune system mouse model with heme oxygenase-1 deficiency.
A challenge for human immune system (HIS) mouse models has been the lack of human red blood cell (hRBC) survival after engraftment of these immune-deficient mice with human CD34+ hematopoietic stem cells (HSCs). This limits the use of HIS models for preclinical testing of targets directed at hRBC-related diseases. Although human white blood cells can develop in the peripheral blood of mice engrafted with human HSCs, peripheral hRBCs are quickly phagocytosed by murine macrophages upon egress from the bone marrow. Genetic ablation of murine myeloid cells results in severe pathology in resulting mice, rendering such an approach to increase hRBC survival in HIS mice impractical. Heme oxygenase-1 (HMOX-1)-deficient mice have reduced macrophages due to toxic buildup of intracellular heme upon engulfment of RBCs, but do not have an overall loss of myeloid cells. We took advantage of this observation and generated HMOX-1-/- mice on a humanized M-CSF/SIRPα/CD47 Rag2-/- IL-2Rγ-/- background. These mice have reduced murine macrophages but comparable levels of murine myeloid cells to HMOX-1+/+ control mice in the same background. Injected hRBCs survive longer in HMOX-1-/- mice than in HMOX-1+/+ controls. Additionally, upon human HSC engraftment, hRBCs can be observed in the peripheral blood of HMOX-1-/- humanized M-CSF/SIRPα/CD47 Rag2-/- IL-2Rγ-/- mice, and hRBC levels can be increased by treatment with human erythropoietin. Given that hRBC are present in the peripheral blood of engrafted HMOX-1-/- mice, these mice have the potential to be used for hematologic disease modeling, and for testing therapeutic treatments for hRBC diseases in vivo.
2023-06-23 | Free heme exacerbates colonic injury induced by anti-cancer therapy.
Gastrointestinal inflammation and bleeding are commonly induced by cancer radiotherapy and chemotherapy but mechanisms are unclear. We demonstrated an increased number of infiltrating heme oxygenase-1 positive (HO-1+) macrophages (Mø, CD68+) and the levels of hemopexin (Hx) in human colonic biopsies from patients treated with radiation or chemoradiation versus non-irradiated controls or in the ischemic intestine compared to matched normal tissues. The presence of rectal bleeding in these patients was also correlated with higher HO-1+ cell infiltration. To functionally assess the role of free heme released in the gut, we employed myeloid-specific HO-1 knockout (LysM-Cre : Hmox1flfl), hemopexin knockout (Hx-/-) and control mice. Using LysM-Cre : Hmox1flfl conditional knockout (KO) mice, we showed that a deficiency of HO-1 in myeloid cells led to high levels of DNA damage and proliferation in colonic epithelial cells in response to phenylhydrazine (PHZ)-induced hemolysis. We found higher levels of free heme in plasma, epithelial DNA damage, inflammation, and low epithelial cell proliferation in Hx-/- mice after PHZ treatment compared to wild-type mice. Colonic damage was partially attenuated by recombinant Hx administration. Deficiency in Hx or Hmox1 did not alter the response to doxorubicin. Interestingly, the lack of Hx augmented abdominal radiation-mediated hemolysis and DNA damage in the colon. Mechanistically, we found an altered growth of human colonic epithelial cells (HCoEpiC) treated with heme, corresponding to an increase in Hmox1 mRNA levels and heme:G-quadruplex complexes-regulated genes such as c-MYC, CCNF, and HDAC6. Heme-treated HCoEpiC cells exhibited growth advantage in the absence or presence of doxorubicin, in contrast to poor survival of heme-stimulated RAW247.6 Mø. In summary, our data indicate that accumulation of heme in the colon following hemolysis and/or exposure to genotoxic stress amplifies DNA damage, abnormal proliferation of epithelial cells, and inflammation as a potential etiology for gastrointestinal syndrome (GIS).
2023-06-10 | Co-administration of angiotensin II and simvastatin triggers kidney injury upon heme oxygenase-1 deficiency
Kidneys are pivotal organ in iron redistribution and can be severely damaged in the course of hemolysis. In our previous studies, we observed that induction of hypertension with angiotensin II (Ang II) combined with simvastatin administration results in a high mortality rate or the appearance of signs of kidney failure in heme oxygenase-1 knockout (HO-1 KO) mice. Here, we aimed to address the mechanisms underlying this effect, focusing on heme and iron metabolism. We show that HO-1 deficiency leads to iron accumulation in the renal cortex. Higher mortality of Ang II and simvastatin-treated HO-1 KO mice coincides with increased iron accumulation and the upregulation of mucin-1 in the proximal convoluted tubules. In vitro studies showed that mucin-1 hampers heme- and iron-related oxidative stress through the sialic acid residues. In parallel, knock-down of HO-1 induces the glutathione pathway in an NRF2-depedent manner, which likely protects against heme-induced toxicity. To sum up, we showed that heme degradation during heme overload is not solely dependent on HO-1 enzymatic activity, but can be modulated by the glutathione pathway. We also identified mucin-1 as a novel redox regulator. The results suggest that hypertensive patients with less active HMOX1 alleles may be at higher risk of kidney injury after statin treatment.
2021-11-15 | CTRP3 protects hippocampal neurons from oxygen-glucose deprivation-induced injury through the AMPK/Nrf2/ARE pathway.
C1q/TNF-related protein 3 (CTRP3), a member of CTRP family, has been found to have neuroprotective effect. In the current study, we investigated the protective role of CTRP3 in hippocampal neurons exposed to oxygen-glucose deprivation/reperfusion (OGD/R). The mRNA and protein levels of CTRP3 in OGD/R-stimulated hippocampal neurons were measured using qRT-PCR and western blot analysis, respectively. CCK-8 assay was performed to assess cell viability. ROS production was measured using the fluorescence probe 2',7'-dichlorofluorescein diacetate (H2DCFDA). The activities of SOD and GPx were determined using ELISA. Cell apoptosis was assessed. Luciferase reporter assay was carried out to assess the activation of ARE). The levels of p-AMPK and Nrf2 were measured using western blot. Our results showed that the expression of CTRP3 was significantly downregulated in hippocampal neuronal cells exposed to OGD/R. Overexpression of CTRP3 improved cell viability of OGD/R-induced hippocampal neurons. In addition, overexpression of CTRP3 attenuated the OGD/R-caused oxidative stress with decreased ROS production and increased activities of SOD and GPx. Moreover, CTRP3 caused a significant increase in bcl-2 expression and decreases in bax expression and caspase-3 activity. Furthermore, CTRP3 overexpression significantly upregulated the levels of p-AMPK and Nrf2, as well induced the activation of ARE in OGD-R-induced hippocampal neurons. CTRP3 upregulated the mRNA expression levels of HO-1, NQO-1 and GPx-3. Additionally, treatment with the inhibitor of AMPK partially reversed the neuroprotective effect of CTRP3 in OGD/R-exposed neurons. CTRP3 exerted protective effect on OGD/R-induced cerebral injury, which was regulated by AMPK/Nrf2/ARE pathway.
2018-02-27 | Transduced PEP-1-Heme Oxygenase-1 Fusion Protein Attenuates Lung Injury in Septic Shock Rats
Oxidative stress and inflammation have been identified to play a vital role in the pathogenesis of lung injury induced by septic shock. Heme oxygenase-1 (HO-1), an effective antioxidant and anti-inflammatory and antiapoptotic substance, has been used for the treatment of heart, lung, and liver diseases. Thus, we postulated that administration of exogenous HO-1 protein transduced by cell-penetrating peptide PEP-1 has a protective role against septic shock-induced lung injury. Septic shock produced by cecal ligation and puncture caused severe lung damage, manifested in the increase in the lung wet/dry ratio, oxidative stress, inflammation, and apoptosis. However, these changes were reversed by treatment with the PEP-1-HO-1 fusion protein, whereas lung injury in septic shock rats was alleviated. Furthermore, the septic shock upregulated the expression of Toll-like receptor 4 (TLR4) and transcription factor NF-κB, accompanied by the increase of lung injury. Administration of PEP-1-HO-1 fusion protein reversed septic shock-induced lung injury by downregulating the expression of TLR4 and NF-κB. Our study indicates that treatment with HO-1 protein transduced by PEP-1 confers protection against septic shock-induced lung injury by its antioxidant, anti-inflammatory, and antiapoptotic effects.
cell therapies
2026-02-10 | STING synergizes with TOX suppressing HO-1 expression to trigger ferroptosis in tumor-infiltrating CD8+ T cell and immunotherapy resistance.
CD8+ T cell abundance within the tumor microenvironment is a critical determinant of immunotherapy efficacy. Here we show that CD8⁺ T cells lacking STING or TOX display markedly improved antitumor activity, with enhanced tumor infiltration and elevated IFN-γ and granzyme B production. These STING or TOX deficient cells exhibit a stem-like transcriptional state and resist ferroptosis by suppressing lipid peroxidation pathways while promoting mitochondrial biogenesis. Mechanistically, STING and TOX form a positive regulatory loop that represses HO-1 expression, leading to iron accumulation, mitochondrial oxidative stress, and ferroptosis in tumor-infiltrating CD8⁺ T cells. We further identify lactate as a microenvironmental trigger of STING-TOX-HO-1-mediated CD8+ T-cell ferroptosis. In mouse tumor models, engineered STING/TOX-deficient CD8⁺ T cells synergize with immune checkpoint blockade, chemotherapy, or STING agonist to enhance tumor control. These findings reveal a central pathway governing CD8⁺ T-cell ferroptosis in tumors and suggest therapeutic strategies to overcome immunotherapy resistance.
2024-11-18 | Fascia-Derived Stem Cells Enhance Fat Graft Retention by Promoting Vascularization through the HMOX1-HIF-1α Pathway
Background: Adipose tissue is a widely used autologous soft tissue filler in plastic surgery, particularly for volumetric restoration in cases of soft tissue deficiency. However, effectively controlling the retention rate of transplanted fat remains a major challenge. Therefore, this study aims to explore strategies to enhance fat graft retention. We isolated fascia-derived stem cells (FDSCs) from human superficial fascia and compared their gene expression profiles with those of adipose-derived stem cells (ADSCs). Through bioinformatics analysis and functional experiments, we identified significant differences in the angiogenic potential of the two cell types. Based on sequencing results, we further investigated the roles of hypoxia-inducible factor-1α (HIF-1α) and heme oxygenase-1 (HMOX1). This study highlights the critical potential of FDSCs in improving fat graft retention and promoting angiogenesis, offering new strategies for enhancing graft survival and optimizing tissue regeneration therapies. Methods: We isolated fascia-derived stem cells (FDSCs) from human superficial fascia and compared them with adipose-derived stem cells (ADSCs). RNA sequencing was performed to analyze gene expression profiles, followed by bioinformatics analysis to identify differences in angiogenic potential. Functional experiments were conducted to investigate the roles of HIF-1α and HMOX1 in angiogenesis. Results: RNA sequencing revealed significant gene expression differences related to angiogenesis in FDSCs. The expression levels of HMOX1, HIF-1α, and VEGFa were significantly higher in FDSCs than in ADSCs, and HMOX1 positively regulated the expression of HIF-1α and VEGFa. In vitro experiments demonstrated that FDSCs promoted angiogenesis more effectively than ADSCs. In vivo co-transplantation experiments further confirmed that FDSCs improved fat graft retention and vascularization. Conclusions: We demonstrated that FDSCs can more effectively promote vascularization both in vitro and in vivo, and significantly improve graft retention, indicating their broad potential for future applications in tissue repair and regeneration.
2022-03-02 | Exosomes derived from mesenchyml stem cells ameliorate oxygen-glucose deprivation/reoxygenation-induced neuronal injury via transferring MicroRNA-194 and targeting Bach1.
The neuroprotective function of miR-194 on neurovascular endothelial cell injury is perceived as a novel method for clinical therapy. So are exosomes (EXs), being attractive in neurofunctional recovery. However, whether EXs derived from mesenchymal stromal cells (MSCs) perform the same efficacy by transferring miR-194 and the underlying mechanism remain vague. This study rooted in oxygen-glucose deprivation/reoxygenation (OGD/R) model. MSCs were isolated by gradient centrifugation and identified by flow cytometry. EXs were obtained through ultracentrifugation, whereas protein levels of specific markers (CD63, TGS101), together with Bach1, Nrf2 and HO-1 were measured by western blot. The relative mRNA expressions of Bach1, NOX1, AGSL4, GPX4 and miR-194 were measured by RT-qPCR assays. Cell viability was measured by cell counting kit-8, and cell migration was detected by wound healing assay. The interaction between miR-194 and Bach1 was predicted by starBase and confirmed by dual luciferase reporter assay. OGD/R dampened cell viability and miR-194 expression. Bach1 could bind with miR-194. miR-194 mimic attenuated the effect of OGD/R on cell viability and protein levels of Nrf2, HO-1 and Bach1, whereas Bach1 overexpression reversed the effect of miR-194 mimics. MSC-EXs could merge with HBMECs. Based on this, MSC-EXs loaded with miR-194 downregulated Bach1 protein level and iron content and the mRNA expressions of NOX1 and ACSL4, yet upregulated miR-194 and GPX4 expressions and Nrf2/HO-1 protein level in OGD/R-injured cells, whereas those carrying ShmiR-194 had the opposite effects. Our study suggested MSC-EXs loaded with miR-194 attenuated OGD/R-induced injury via targeting Bach1, providing a new therapeutic strategy for cerebral injuries.
2019-12-29 | Heme oxygenase‐1 deficiency triggers exhaustion of hematopoietic stem cells
While intrinsic changes in aging hematopoietic stem cells (HSCs) are well characterized, it remains unclear how extrinsic factors affect HSC aging. Here, we demonstrate that cells in the niche-endothelial cells (ECs) and CXCL12-abundant reticular cells (CARs)-highly express the heme-degrading enzyme, heme oxygenase 1 (HO-1), but then decrease its expression with age. HO-1-deficient animals (HO-1-/- ) have altered numbers of ECs and CARs that produce less hematopoietic factors. HSCs co-cultured in vitro with HO-1-/- mesenchymal stromal cells expand, but have altered kinetic of growth and differentiation of derived colonies. HSCs from young HO-1-/- animals have reduced quiescence and regenerative potential. Young HO-1-/- HSCs exhibit features of premature exhaustion on the transcriptional and functional level. HO-1+/+ HSCs transplanted into HO-1-/- recipients exhaust their regenerative potential early and do not reconstitute secondary recipients. In turn, transplantation of HO-1-/- HSCs to the HO-1+/+ recipients recovers the regenerative potential of HO-1-/- HSCs and reverses their transcriptional alterations. Thus, HSC-extrinsic activity of HO-1 prevents HSCs from premature exhaustion and may restore the function of aged HSCs.
2019-09-04 | Infused wild-type macrophages reside and self-renew in the liver to rescue the hemolysis and anemia of Hmox1-deficient mice.
Heme oxygenase 1 (HMOX1), the inducible enzyme that catabolizes the degradation of heme into biliverdin, iron, and carbon monoxide, plays an essential role in the clearance of senescent and damaged red blood cells, systemic iron homeostasis, erythropoiesis, vascular hemostasis, and oxidative and inflammatory stress responses. In humans, HMOX1 deficiency causes a rare and lethal disease, characterized by severe anemia, intravascular hemolysis, as well as vascular and tissue damage. Hmox1 knockout (KO) mice recapitulated the phenotypes of HMOX1-deficiency patients and could be rescued by bone marrow (BM) transplantation that engrafted donor's hematopoietic stem cells into the recipient animals after myeloablation. To find better therapy and elucidate the contribution of macrophages to the pathogenesis of HMOX1-deficiency disease, we infused wild-type (WT) macrophages into Hmox1 KO mice. Results showed that WT macrophages engrafted and proliferated in the livers of Hmox1 KO mice, which corrected the microcytic anemia, rescued the intravascular hemolysis, restored iron homeostasis, eliminated kidney iron overload and tissue damage, and provided long-term protection. These results showed that a single macrophage infusion delivered a long-term curative effect in Hmox1 KO mice, obviating the need for BM transplantation, and suggested that the HMOX1 disease stems mainly from the loss of viable reticuloendothelial macrophages. Our work provides new insights into the etiology of HMOX1 deficiency and demonstrates the potential of infusion of WT macrophages to prevent disease in patients with HMOX1 deficiency and potentially other macrophage-related diseases.
small molecules
2026-05-15 | Heme Metabolism-Derived Carbon Monoxide Regulates Skeletal Muscle Function.
Heme oxygenases, HO-1 (Hmox1) and HO-2 (Hmox2), regulate skeletal muscle homeostasis by degrading heme and generating carbon monoxide (CO), a bioactive signalling molecule. Although HO-1 is known to influence muscle fibre composition and mitochondrial function, the role of HO-2 in activity-dependent neuromuscular plasticity remains poorly understood. This study aimed to define the distinct contributions of each isoform and test whether CO could restore muscle function in HO-deficient states. We generated Hmox1/2 double-knockout mice (Hmox1/2-/-) and compared their skeletal muscle phenotype with that of single HO-1 or HO-2 knockouts and wild-type (WT) controls under sedentary and exercised conditions. We evaluated endurance capacity using treadmill running (n = 8-12 per group), assessed fibre-type distribution and neuromuscular junction (NMJ) morphology via immunohistochemistry and measured mitochondrial function using high-resolution respirometry. Primary neuronal cultures were analysed using multielectrode array recordings to assess firing dynamics. Inhaled CO was administered to test its capacity to rescue muscle phenotype and performance. HO-1 deficiency led to a significant reduction in oxidative fibres (Type I and IIa), decreased mitochondrial respiratory capacity (reduced by ~30%, p < 0.01) and diminished treadmill endurance (-40% running time vs. WT, p < 0.001). Hmox2 deficiency was associated with NMJ remodelling, increased acetylcholine receptor expression, reduced Sox2 transcription and heightened burst firing. The double deletion of HO-1/HO-2 produced an additive phenotype characterized by severe mitochondrial dysfunction, increased glycolytic fibre content and NMJ remodelling. We identify CO, a by-product of HO-1, as a crucial modulator of skeletal muscle adaptation, capable of compensating for HO deficiency. Treatment with CO in Hmox1/2-/- mice restored fibre-type distribution toward oxidative fibres (increased by 25%, p < 0.01), improved mitochondrial respiratory parameters and doubled endurance performance (p < 0.001). CO also normalized mitochondrial protein expression and modulated key metabolic pathways, including nucleotide metabolism, the TCA cycle and redox balance. HO-1 and HO-2 have distinct roles in regulating muscle phenotype and metabolic adaptation. HO-1 modulates mitochondrial content and muscle plasticity, whereas Hmox2 regulates, in part, activity-dependent neuromuscular plasticity and responsiveness to exercise. Exogenous CO effectively restores mitochondrial and functional deficits in HO-deficient muscle, mimicking endurance exercise adaptations. These findings support the therapeutic potential of CO in conditions of muscle disuse, aging or disease where exercise is limited or not feasible.
2025-12-18 | Epithelial HO-1 regulates iron availability and promotes colonic tumorigenesis in a context-dependent manner.
Induction of heme oxygenase-1 (HO-1/Hmox1) is broadly considered cytoprotective, but the role of colonic epithelial HO-1 in colitis-associated tumorigenesis is poorly defined. HO-1 catabolizes heme, releasing ferrous iron, a key driver of oxidative stress and lipid peroxidation. We observed that colonic epithelial HO-1 was induced during colitis and tumorigenesis. We also found that HO-1 was upregulated in ferroptosis-inducing conditions in murine and human colonic epithelial organoids and correlated with lipid peroxidation and ferroptosis markers in colonic tumors. In colonic epithelial organoids exposed to heme, deletion of Hmox1 amplified a compensatory oxidative stress and detoxification transcriptional program, likely reflecting unresolved oxidative and nonoxidative toxicity from heme. In vivo, epithelial HO-1-deficient mice developed significantly fewer and smaller tumors compared with littermate controls in a colitis-associated tumorigenesis model, despite similar inflammatory injury. Tumors from KO mice exhibited reduced iron levels, decreased lipid peroxidation, lower oxidative DNA damage, and decreased proliferation. Single-cell RNA sequencing of tumor epithelial cells revealed a shift from a proliferative to a stress-adaptive program with loss of HO-1. These findings identify epithelial HO-1 as a context-dependent regulator of tumorigenesis: it is protective against acute heme toxicity but promotes iron-dependent oxidative damage and proliferation in the setting of chronic inflammation.
2025-11-11 | The neonicotinoid Imidacloprid provokes Ferritinophagy/Ferroptosis Axis disruption in rats' liver: The attenuation impact of Berberine chloride-loaded nano-liposomes.
Imidacloprid (IMI) is a widely applied insecticide, with evidence linking chronic exposure to toxic effects, particularly hepatotoxicity. Recently, ferroptosis has been nominated as a new contributor to hepatotoxicity-related cell death. This study was designed to investigate whether ferroptosis and ferritinophagy are involved in IMI-induced liver injury and to explore the potential protective effect of berberine chloride-PEGylated lipid nanoparticles (BC-PL). Berberine is a well-known alkaloid with documented hepatoprotective activity. Accordingly, adult male rats in six groups were administered two doses of IMI (22.5 and 45 mg/kg), with or without 10 mg/kg of BC-PL daily for 30 days. Liver enzymes, hepatic ferrous (Fe2+) levels, markers of oxidative stress, inflammation, ferritinophagy, and ferroptosis, as well as morphological changes, were analyzed. IMI significantly elevated liver enzymes, hepatic Fe2+, oxidative stress, and inflammatory markers. It also adversely affected the expression of ferritinophagy and ferroptosis markers, upregulating nuclear receptor coactivator 4 (NCOA4), ferritin heavy chain (FTH-1), transferrin receptor 1 (TFR1), and Keap1, while downregulating glutathione peroxidase (GPx), solute carrier family 7 member 11 (SLC7A11), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). IMI-induced hepatotoxicity was further confirmed by light and electron microscopy, and hepatic injury was directly associated with IMI dosage. Administration of BC-PL mitigated IMI-induced liver damage, as evidenced by improvements in biochemical and histopathological changes. This study thus sheds light on the possible role of the ferritinophagy/ferroptosis axis in IMI-induced hepatotoxicity, and that the inhibition of ferritinophagy contributes to the efficacy of BC-PL as a nano-formulated hepatoprotective system.
2025-10-27 | Iron Deficiency Aggravates Hepatic Inflammation via Endoplasmic Reticulum Stress-Driven NF-κB Pathway Activation in Suckling Piglets
Iron deficiency (ID) imposes a significant health burden on infants and suckling piglets, yet its impact on hepatic inflammatory injury remains poorly defined. This study combined in vivo and in vitro models to investigate the underlying mechanisms. In piglets, iron deficiency triggered hepatic oxidative stress by inducing a redox imbalance and suppressing the core Nrf2/HO-1 antioxidant signaling pathway. Histopathological examination revealed structural abnormalities in ID piglet livers, including disorganized hepatic cords, cytoplasmic vacuolation, hydropic degeneration, and mononuclear inflammatory cell infiltration. Transmission electron microscopy further showed shrunk nuclear envelopes, reduced numbers of rough endoplasmic reticulum (RER), and dilated RER cisternae in hepatocytes from ID piglets. Mechanistically, ID activated endoplasmic reticulum stress (ERS) and the PERK/IRE1α branches of the unfolded protein response. RNA-seq transcriptomic analysis demonstrated significant dysregulation of immune-related pathways, accompanied by elevated pro-inflammatory cytokines (e.g.,interleukin-1 beta, IL-1β, tumor necrosis factor-alpha, TNF-α) and decreased anti-inflammatory cytokines (e.g., interleukin 4, IL-4, interleukin-10, IL-10). Central to this inflammatory response was the activation of the TLR4/NF-κB pathway, evidenced by upregulation of MyD88 and increased phosphorylation of IκBα and NF-κB p65. In vitro, deferoxamine (DFO)-induced ID in hepatocytes consistently recapitulated the key features of this phenotype, including the activation of ERS/ UPR and the TLR4/NF-κB signaling pathway. Critically, pharmacological inhibition of ERS by 4-phenylbutyrate (4-PBA) attenuated DFO-induced NF-κB activation and restored pro-/anti-inflammatory cytokine balance. In conclusion, these findings demonstrate that ID exacerbates hepatic inflammation through ERS-mediated activation of NF-κB pathway, providing novel mechanistic insights into liver injury associated with ID.
2025-10-18 | Med20 regulates myelination in the peripheral nervous system by modulating ferroptosis of Schwann cells.
Myelin sheath is essential for the maintenance of neural system functions. The mediator complex (MED) is associated with neurodegenerative diseases. Mutation of the MED subunit Med20 leads to abnormal brain development, but whether Med20 modulates myelination remains unknown. In this study, we report that Med20 is an important modulator of myelination in the peripheral nervous system. Loss of Med20 in Schwann cells (SCs) induces ferroptosis, thus impairing myelination. The functions of Med20 in SCs are mediated by its downstream target DDB1. DDB1 controls SC ferroptosis by regulating Hmox1 through a "DDB1-UHRF1-BACH1-Hmox1" transcription regulation axis and its direct interaction and subsequent simultaneous ubiquitination of the HO-1 protein. HO-1 inhibitor ZnPP or ferroptosis inhibitor Fer-1 is sufficient and efficient for antagonizing ferroptosis in SCs and restoring myelination in Med20-deficient mice. The results of our study reveal that Med20 is an important regulator in the network that controls myelination in the peripheral nervous system.
gene therapies
2025-05-03 | The NRF2/HO- 1 Pathway: a Potential Regulatory Factor in Fluoride-Induced Colonic Injury under Estrogen Deficiency.
Our previous studies have demonstrated that fluoride (F) overexposure is a risk factor for colonic microenvironment, yet its underlying mechanisms and the influencing factors remain poorly understood. Here, a rat model of F exposure (0, 25, 50, 100 mg/L in drinking water) combined with ovariectomy (OVX)-induced estrogen deficiency was established to investigate the roles of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in F-induced colonic damage under the state of estrogen deficiency. Result showed that F exposure significantly reduced occludin and claudin-1 expression, further resulting in the colon's morphology impairment. Concurrently, F suppressed epithelial proliferation, decreased goblet cell numbers, and diminished short-chain fatty acid (SCFA) production. OVX-induced estrogen deficiency exacerbated F-induced colonic barrier damage and SCFA decreased. Mechanistically, estrogen deficiency aggravated F intestinal toxicity by further inhibiting the protein expression of Nrf2 and HO-1 and upregulating Keap1 protein expression, following downregulated Bcl-2 mRNA levels and upregulated Bax and caspase-3 mRNA levels, and promoting colonic epithelial cell apoptosis. These findings identify that Nrf2/HO-1 key protein disorders are involved in F-induced colonic barrier injury, and estrogen deficiency further aggravated F intestinal toxicity.
2019-07-29 | Deletion of HO-1 blocks development of B lymphocytes in mice
B lymphocytes, a key cluster of cells composing the immune system, can protect against abnormal biological factors. Heme oxygenase-1 (HO-1) plays important roles in cell proliferation and immune regulation, but its effects on the development and growth of B lymphocytes are still unknown. Herein, the count of B lymphocytes in HO-1 gene knockout (HO-1+/−) mice was significantly lower than that of the HO-1 gene wild-type (HO-1WT) mice. Meanwhile, the cell count of HO-1+/− mice did not recover after irradiation for one week, due to the G0/G1 phase arrest of Pro-B cells and the augmented apoptosis of Pre-B cells. Up-regulation of HO-1 by lentivirus attenuated the Pro-B cell cycle arrest and Pre-B cell apoptosis. To understand the molecular mechanism by which HO-1 knockout blocked B lymphocyte development, protein-to-protein interaction network and Western blot were used. The PI3K/AKT signaling pathway mediated the regulatory effects of HO-1 on B lymphocytes. In conclusion, HO-1 is a crucial transcriptional repressor for B cell development.
2016-07-19 | Proximal tubule-targeted heme oxygenase-1 in cisplatin-induced acute kidney injury.
Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that catalyzes the breakdown of heme to biliverdin, carbon monoxide, and iron. The beneficial effects of HO-1 expression are not merely due to degradation of the pro-oxidant heme but are also credited to the by-products that have potent, protective effects, including antioxidant, anti-inflammatory, and prosurvival properties. This is well reflected in the preclinical animal models of injury in both renal and nonrenal settings. However, excessive accumulation of the by-products can be deleterious and lead to mitochondrial toxicity and oxidative stress. Therefore, use of the HO system in alleviating injury merits a targeted approach. Based on the higher susceptibility of the proximal tubule segment of the nephron to injury, we generated transgenic mice using cre-lox technology to enable manipulation of HO-1 (deletion or overexpression) in a cell-specific manner. We demonstrate the validity and feasibility of these mice by breeding them with proximal tubule-specific Cre transgenic mice. Similar to previous reports using chemical modulators and global transgenic mice, we demonstrate that whereas deletion of HO-1, specifically in the proximal tubules, aggravates structural and functional damage during cisplatin nephrotoxicity, selective overexpression of HO-1 in proximal tubules is protective. At the cellular level, cleaved caspase-3 expression, a marker of apoptosis, and p38 signaling were modulated by HO-1. Use of these transgenic mice will aid in the evaluation of the effects of cell-specific HO-1 expression in response to injury and assist in the generation of targeted approaches that will enhance recovery with reduced, unwarranted adverse effects.
2016-02-24 | Heme oxygenase-1 regulates mitochondrial quality control in the heart
The cardioprotective inducible enzyme heme oxygenase-1 (HO-1) degrades prooxidant heme into equimolar quantities of carbon monoxide, biliverdin, and iron. We hypothesized that HO-1 mediates cardiac protection, at least in part, by regulating mitochondrial quality control. We treated WT and HO-1 transgenic mice with the known mitochondrial toxin, doxorubicin (DOX). Relative to WT mice, mice globally overexpressing human HO-1 were protected from DOX-induced dilated cardiomyopathy, cardiac cytoarchitectural derangement, and infiltration of CD11b+ mononuclear phagocytes. Cardiac-specific overexpression of HO-1 ameliorated DOX-mediated dilation of the sarcoplasmic reticulum as well as mitochondrial disorganization in the form of mitochondrial fragmentation and increased numbers of damaged mitochondria in autophagic vacuoles. HO-1 overexpression promotes mitochondrial biogenesis by upregulating protein expression of NRF1, PGC1α, and TFAM, which was inhibited in WT animals treated with DOX. Concomitantly, HO-1 overexpression inhibited the upregulation of the mitochondrial fission mediator Fis1 and resulted in increased expression of the fusion mediators, Mfn1 and Mfn2. It also prevented dynamic changes in the levels of key mediators of the mitophagy pathway, PINK1 and parkin. Therefore, these findings suggest that HO-1 has a novel role in protecting the heart from oxidative injury by regulating mitochondrial quality control.
2015-12-16 | A new model of an arteriovenous fistula in chronic kidney disease in the mouse: beneficial effects of upregulated heme oxygenase-1
The arteriovenous fistula (AVF) is the preferred hemodialysis vascular access, but it is complicated by high failure rates and attendant morbidity. This study provides the first description of a murine AVF model that recapitulates two salient features of hemodialysis AVFs, namely, anastomosis of end-vein to side-artery to create the AVF and the presence of chronic kidney disease (CKD). CKD reduced AVF blood flow, observed as early as 3 days after AVF creation, and increased neointimal hyperplasia, venous wall thickness, thrombus formation, and vasculopathic gene expression in the AVF. These adverse effects of CKD could not be ascribed to preexisting alterations in blood pressure or vascular reactivity in this CKD model. In addition to vasculopathic genes, CKD induced potentially vasoprotective genes in the AVF such as heme oxygenase-1 (HO-1) and HO-2. To determine whether prior HO-1 upregulation may protect in this model, we upregulated HO-1 by adeno-associated viral gene delivery, achieving marked venous induction of the HO-1 protein and HO activity. Such HO-1 upregulation improved AVF blood flow and decreased venous wall thickness in the AVF. Finally, we demonstrate that the administration of carbon monoxide, a product of HO, acutely increased AVF blood flow. This study thus demonstrates: 1) the feasibility of a clinically relevant murine AVF model created in the presence of CKD and involving an end-vein to side-artery anastomosis; 2) the exacerbatory effect of CKD on clinically relevant features of this model; and 3) the beneficial effects in this model conferred by HO-1 upregulation by adeno-associated viral gene delivery.
proteins
2024-09-30 | Peripheral human red blood cell development in human immune system mouse model with heme oxygenase-1 deficiency.
A challenge for human immune system (HIS) mouse models has been the lack of human red blood cell (hRBC) survival after engraftment of these immune-deficient mice with human CD34+ hematopoietic stem cells (HSCs). This limits the use of HIS models for preclinical testing of targets directed at hRBC-related diseases. Although human white blood cells can develop in the peripheral blood of mice engrafted with human HSCs, peripheral hRBCs are quickly phagocytosed by murine macrophages upon egress from the bone marrow. Genetic ablation of murine myeloid cells results in severe pathology in resulting mice, rendering such an approach to increase hRBC survival in HIS mice impractical. Heme oxygenase-1 (HMOX-1)-deficient mice have reduced macrophages due to toxic buildup of intracellular heme upon engulfment of RBCs, but do not have an overall loss of myeloid cells. We took advantage of this observation and generated HMOX-1-/- mice on a humanized M-CSF/SIRPα/CD47 Rag2-/- IL-2Rγ-/- background. These mice have reduced murine macrophages but comparable levels of murine myeloid cells to HMOX-1+/+ control mice in the same background. Injected hRBCs survive longer in HMOX-1-/- mice than in HMOX-1+/+ controls. Additionally, upon human HSC engraftment, hRBCs can be observed in the peripheral blood of HMOX-1-/- humanized M-CSF/SIRPα/CD47 Rag2-/- IL-2Rγ-/- mice, and hRBC levels can be increased by treatment with human erythropoietin. Given that hRBC are present in the peripheral blood of engrafted HMOX-1-/- mice, these mice have the potential to be used for hematologic disease modeling, and for testing therapeutic treatments for hRBC diseases in vivo.
2023-06-23 | Free heme exacerbates colonic injury induced by anti-cancer therapy.
Gastrointestinal inflammation and bleeding are commonly induced by cancer radiotherapy and chemotherapy but mechanisms are unclear. We demonstrated an increased number of infiltrating heme oxygenase-1 positive (HO-1+) macrophages (Mø, CD68+) and the levels of hemopexin (Hx) in human colonic biopsies from patients treated with radiation or chemoradiation versus non-irradiated controls or in the ischemic intestine compared to matched normal tissues. The presence of rectal bleeding in these patients was also correlated with higher HO-1+ cell infiltration. To functionally assess the role of free heme released in the gut, we employed myeloid-specific HO-1 knockout (LysM-Cre : Hmox1flfl), hemopexin knockout (Hx-/-) and control mice. Using LysM-Cre : Hmox1flfl conditional knockout (KO) mice, we showed that a deficiency of HO-1 in myeloid cells led to high levels of DNA damage and proliferation in colonic epithelial cells in response to phenylhydrazine (PHZ)-induced hemolysis. We found higher levels of free heme in plasma, epithelial DNA damage, inflammation, and low epithelial cell proliferation in Hx-/- mice after PHZ treatment compared to wild-type mice. Colonic damage was partially attenuated by recombinant Hx administration. Deficiency in Hx or Hmox1 did not alter the response to doxorubicin. Interestingly, the lack of Hx augmented abdominal radiation-mediated hemolysis and DNA damage in the colon. Mechanistically, we found an altered growth of human colonic epithelial cells (HCoEpiC) treated with heme, corresponding to an increase in Hmox1 mRNA levels and heme:G-quadruplex complexes-regulated genes such as c-MYC, CCNF, and HDAC6. Heme-treated HCoEpiC cells exhibited growth advantage in the absence or presence of doxorubicin, in contrast to poor survival of heme-stimulated RAW247.6 Mø. In summary, our data indicate that accumulation of heme in the colon following hemolysis and/or exposure to genotoxic stress amplifies DNA damage, abnormal proliferation of epithelial cells, and inflammation as a potential etiology for gastrointestinal syndrome (GIS).
2023-06-10 | Co-administration of angiotensin II and simvastatin triggers kidney injury upon heme oxygenase-1 deficiency
Kidneys are pivotal organ in iron redistribution and can be severely damaged in the course of hemolysis. In our previous studies, we observed that induction of hypertension with angiotensin II (Ang II) combined with simvastatin administration results in a high mortality rate or the appearance of signs of kidney failure in heme oxygenase-1 knockout (HO-1 KO) mice. Here, we aimed to address the mechanisms underlying this effect, focusing on heme and iron metabolism. We show that HO-1 deficiency leads to iron accumulation in the renal cortex. Higher mortality of Ang II and simvastatin-treated HO-1 KO mice coincides with increased iron accumulation and the upregulation of mucin-1 in the proximal convoluted tubules. In vitro studies showed that mucin-1 hampers heme- and iron-related oxidative stress through the sialic acid residues. In parallel, knock-down of HO-1 induces the glutathione pathway in an NRF2-depedent manner, which likely protects against heme-induced toxicity. To sum up, we showed that heme degradation during heme overload is not solely dependent on HO-1 enzymatic activity, but can be modulated by the glutathione pathway. We also identified mucin-1 as a novel redox regulator. The results suggest that hypertensive patients with less active HMOX1 alleles may be at higher risk of kidney injury after statin treatment.
2021-11-15 | CTRP3 protects hippocampal neurons from oxygen-glucose deprivation-induced injury through the AMPK/Nrf2/ARE pathway.
C1q/TNF-related protein 3 (CTRP3), a member of CTRP family, has been found to have neuroprotective effect. In the current study, we investigated the protective role of CTRP3 in hippocampal neurons exposed to oxygen-glucose deprivation/reperfusion (OGD/R). The mRNA and protein levels of CTRP3 in OGD/R-stimulated hippocampal neurons were measured using qRT-PCR and western blot analysis, respectively. CCK-8 assay was performed to assess cell viability. ROS production was measured using the fluorescence probe 2',7'-dichlorofluorescein diacetate (H2DCFDA). The activities of SOD and GPx were determined using ELISA. Cell apoptosis was assessed. Luciferase reporter assay was carried out to assess the activation of ARE). The levels of p-AMPK and Nrf2 were measured using western blot. Our results showed that the expression of CTRP3 was significantly downregulated in hippocampal neuronal cells exposed to OGD/R. Overexpression of CTRP3 improved cell viability of OGD/R-induced hippocampal neurons. In addition, overexpression of CTRP3 attenuated the OGD/R-caused oxidative stress with decreased ROS production and increased activities of SOD and GPx. Moreover, CTRP3 caused a significant increase in bcl-2 expression and decreases in bax expression and caspase-3 activity. Furthermore, CTRP3 overexpression significantly upregulated the levels of p-AMPK and Nrf2, as well induced the activation of ARE in OGD-R-induced hippocampal neurons. CTRP3 upregulated the mRNA expression levels of HO-1, NQO-1 and GPx-3. Additionally, treatment with the inhibitor of AMPK partially reversed the neuroprotective effect of CTRP3 in OGD/R-exposed neurons. CTRP3 exerted protective effect on OGD/R-induced cerebral injury, which was regulated by AMPK/Nrf2/ARE pathway.
2018-02-27 | Transduced PEP-1-Heme Oxygenase-1 Fusion Protein Attenuates Lung Injury in Septic Shock Rats
Oxidative stress and inflammation have been identified to play a vital role in the pathogenesis of lung injury induced by septic shock. Heme oxygenase-1 (HO-1), an effective antioxidant and anti-inflammatory and antiapoptotic substance, has been used for the treatment of heart, lung, and liver diseases. Thus, we postulated that administration of exogenous HO-1 protein transduced by cell-penetrating peptide PEP-1 has a protective role against septic shock-induced lung injury. Septic shock produced by cecal ligation and puncture caused severe lung damage, manifested in the increase in the lung wet/dry ratio, oxidative stress, inflammation, and apoptosis. However, these changes were reversed by treatment with the PEP-1-HO-1 fusion protein, whereas lung injury in septic shock rats was alleviated. Furthermore, the septic shock upregulated the expression of Toll-like receptor 4 (TLR4) and transcription factor NF-κB, accompanied by the increase of lung injury. Administration of PEP-1-HO-1 fusion protein reversed septic shock-induced lung injury by downregulating the expression of TLR4 and NF-κB. Our study indicates that treatment with HO-1 protein transduced by PEP-1 confers protection against septic shock-induced lung injury by its antioxidant, anti-inflammatory, and antiapoptotic effects.
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