Hypoxia-Induced Mechanisms in Liver Disease

Chronic liver disease often features regions of reduced oxygen supply, or hypoxia, which trigger adaptive and maladaptive responses in multiple cell types. Hepatocytes activate hypoxia-inducible factor-1α (HIF-1α), altering lipid metabolism and promoting fibrogenic signalling through transforming growth factor-β and other profibrotic mediators. Kupffer cells and recruited macrophages respond to hypoxia by releasing inflammatory cytokines, exacerbating oxidative stress and further stabilising HIF-1α. In parallel, hepatic stellate cells sense hypoxic stress and transdifferentiate into myofibroblasts, depositing excess extracellular matrix. Dysregulated peroxisomal β-oxidation under hypoxia contributes to lipid accumulation and lipotoxicity, while reactive oxygen species amplify injury and may precipitate ferroptotic cell death. Sustained hypoxia also fosters angiogenesis and a microenvironment conducive to neoplastic transformation, linking chronic fibrogenesis to carcinogenesis.

Research from Nature Portfolio

A novel nanosystem combines manganese dioxide with sustained-release Saikosaponin b1 to decompose excess hydrogen peroxide into oxygen, alleviating local hypoxia and inhibiting activation of hepatic stellate cells, thereby reducing fibrotic progression. This approach enhances antifibrotic efficacy by restoring catalase-like activity and counteracting hypoxia-driven TGF-β1 induction. In a complementary study, loss of hepatocyte HIF-1α in a choline-deficient diet model accelerated steatosis by impairing induction of lipin1, a regulator of peroxisomal β-oxidation. Restoring lipin1 activity via HIF-1α signalling mitigated triglyceride accumulation and highlighted the central role of hypoxia-responsive transcriptional programmes in maintaining lipid homeostasis.

Hypoxia-Induced Mechanisms in Liver Disease publication trend

The graph below shows the total number of articles in hypoxia-induced mechanisms in liver disease across all publications each year (not limited to Nature Index journals).

Technical terms

Hypoxia-inducible factor-1α (HIF-1α): key transcription factor activated in low-oxygen conditions, orchestrating cellular adaptation to hypoxia.

Ferroptosis: regulated cell death driven by iron-dependent lipid peroxidation, implicated in hypoxia-related liver injury.

Hepatic stellate cell: perisinusoidal cell that converts into fibrogenic myofibroblasts upon chronic liver injury and hypoxic stress.

Peroxisomal β-oxidation: metabolic pathway within peroxisomes for very-long-chain fatty acid degradation, modulated by hypoxia-responsive transcription factors.

References

1. Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis. Cells (2021).
2. Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease. PLOS ONE (2016).
3. Hypoxia-Inducible Factor-1alpha and MAPK Co-Regulate Activation of Hepatic Stellate Cells upon Hypoxia Stimulation. PLOS ONE (2013).
4. Nanodrug rescues liver fibrosis via synergistic therapy with H2O2 depletion and Saikosaponin b1 sustained release. Communications Biology (2023).
5. HIF-1-dependent lipin1 induction prevents excessive lipid accumulation in choline-deficient diet-induced fatty liver. Scientific Reports (2018).
6. IL6 Derived from Macrophages under Intermittent Hypoxia Exacerbates NAFLD by Promoting Ferroptosis via MARCH3‐Led Ubiquitylation of GPX4. Advanced Science (2024).
7. The protease activated receptor 2 - CCAAT/enhancer-binding protein beta - SerpinB3 axis inhibition as a novel strategy for the treatment of non-alcoholic steatohepatitis. Molecular Metabolism (2024).
8. Histidine-rich glycoprotein in metabolic dysfunction-associated steatohepatitis-related disease progression and liver carcinogenesis. Frontiers in Immunology (2024).