Pathophysiological and Cellular Mechanisms of Liver Fibrosis

Liver fibrosis is the end-result of chronic hepatic injury arising from viral, metabolic, alcoholic or autoimmune insults. The central event is activation of hepatic stellate cells, which transdifferentiate into myofibroblast-like cells that secrete excessive extracellular matrix (ECM), disrupting normal lobular architecture. Cross-talk between injured hepatocytes, Kupffer cells and sinusoidal endothelial cells sustains a pro-fibrogenic milieu through cytokines (notably transforming growth factor-β and platelet-derived growth factor), chemokines and reactive oxygen species. Immune cells amplify this response by producing inflammatory mediators that drive stellate cell proliferation and survival. Sinusoidal capillarisation and vascular remodelling further impair nutrient exchange and perpetuate hypoxia, reinforcing ECM deposition. Over time, parenchymal extinction and nodule formation lead to cirrhosis, portal hypertension and risk of hepatocellular carcinoma. Recent insights have highlighted the dynamic balance between profibrotic signals and matrix‐degrading pathways, revealing potential windows for therapeutic intervention that aim to reverse stellate cell activation, restore endothelial fenestrations and promote ECM degradation.

Research from Nature Portfolio

Recent studies have elucidated a novel Sonic hedgehog–heat shock protein 90β axis in nonalcoholic steatohepatitis. In this work, hedgehog ligand stimulation stabilises HSP90β in hepatocytes via decreased ubiquitylation, leading to secretion of HSP90β-rich exosomes bearing miR-28-5p. These exosomes target Rap1b in macrophages, enhancing NF-κB-driven inflammation and fibrosis. Pharmacological or genetic disruption of this axis attenuates steatohepatitic injury and fibrogenesis in mouse models and correlates with elevated serum miR-28-5p in human patients, pointing to both therapeutic targets and diagnostic biomarkers. Foundational research on amphiregulin has demonstrated its fibrogenic role in human hepatic stellate cells. Amphiregulin engages EGFR and downstream PI3K and p38 pathways to stimulate stellate cell proliferation, collagen synthesis and resistance to apoptosis. Expression of amphiregulin and its activating protease is increased in mouse and human nonalcoholic steatohepatitis, suggesting that antagonising this growth factor could mitigate matrix accumulation in metabolic liver disease.

Pathophysiological and Cellular Mechanisms of Liver Fibrosis publication trend

The graph below shows the total number of articles in pathophysiological and cellular mechanisms of liver fibrosis across all publications each year (not limited to Nature Index journals).

Technical terms

Hepatic stellate cell (HSC): A perisinusoidal cell in the liver that becomes activated into a myofibroblast-like cell upon injury, producing extracellular matrix.

Extracellular matrix (ECM): A network of collagen and other proteins that provides structural support; excessive ECM in the liver leads to fibrosis.

Myofibroblast: A contractile, matrix-secreting cell type derived from activated HSCs, central to fibrotic scar formation.

Nonalcoholic steatohepatitis (NASH): An advanced form of fatty liver disease marked by inflammation and hepatocyte injury, often preceding fibrosis.

Sonic hedgehog (SHH) pathway: A signalling cascade involving hedgehog ligands and Smoothened receptor that regulates cellular proliferation and repair responses.

Transforming growth factor-β (TGFβ): A cytokine that drives fibrogenesis by inducing HSC activation and ECM gene expression.

Senescence-associated secretome: A collection of factors released by senescent cells that can perpetuate inflammation and tissue remodelling.

References

1. Sonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice. Nature Communications (2024).
2. The senescence-associated secretome of hedgehog-deficient hepatocytes drives MASLD progression. Journal of Clinical Investigation (2024).
3. Mechanisms of liver fibrosis and its role in liver cancer. Experimental Biology and Medicine (2020).
4. Cellular Mechanisms of Liver Fibrosis. Frontiers in Pharmacology (2021).
5. Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation. Biomedicines (2021).
6. Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis. Scientific Reports (2015).