Hepatic Stellate Cell Activation in Liver Fibrosis Mechanisms

Liver fibrosis arises when chronic injury disrupts normal hepatic architecture and function. Central to this process are hepatic stellate cells (HSCs), which in a quiescent state store vitamin A but, upon exposure to inflammatory mediators and oxidative stress, transdifferentiate into proliferative, contractile myofibroblasts. These activated HSCs secrete excessive extracellular matrix (ECM) proteins, notably type I collagen, leading to scar formation and impaired liver function. Activation is orchestrated by a network of profibrogenic cytokines—chiefly transforming growth factor-β (TGF-β)—reactive oxygen species and mechanical cues from the altered microenvironment. Concurrently, HSCs undergo profound metabolic reprogramming, shifting towards aerobic glycolysis and enhanced lipid and amino-acid turnover to meet bioenergetic and biosynthetic demands. Cross-talk with resident and infiltrating immune cells further amplifies fibrogenic signalling, whilst epigenetic modifiers and autophagy pathways refine the activation programme. Importantly, recent evidence has highlighted the inherent heterogeneity of HSC populations across the lobule and the potential for fibrosis regression upon removal of injurious stimuli, underscoring both the complexity and therapeutic promise of targeting HSC activation in diverse liver diseases worldwide.

Research from Nature Portfolio

Recent studies have demonstrated that inhibition of specific immune cell subsets can indirectly attenuate HSC activation and promote regression of established fibrosis. By targeting mucosal-associated invariant T (MAIT) cells, researchers achieved a shift in monocyte-derived macrophage phenotypes from pro-fibrogenic to restorative, accompanying reduced ECM deposition and enhanced autophagy in both macrophages and HSCs. In parallel, work on mitochondria-derived damage-associated molecular patterns (mito-DAMPs) has revealed that injured hepatocytes release mtDNA-rich signals which directly engage HSCs, triggering their activation and driving collagen production. These findings identify critical immune-fibrosis axes and suggest novel antifibrotic strategies aimed at modulating intercellular communication and danger signal release.

Hepatic Stellate Cell Activation in Liver Fibrosis Mechanisms publication trend

The graph below shows the total number of articles in hepatic stellate cell activation in liver fibrosis mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Hepatic stellate cell (HSC): a pericyte in the liver that, when activated by injury, becomes a collagen-secreting myofibroblast involved in scar formation.

Extracellular matrix (ECM): a complex network of proteins and polysaccharides that provides structural support to tissues; excessive ECM deposition defines fibrosis.

Myofibroblast: an activated, contractile fibroblast-like cell that produces high levels of ECM proteins during wound healing and fibrosis.

Damage-associated molecular pattern (DAMP): an endogenous molecule released by stressed or dying cells that triggers inflammatory and fibrogenic responses.

Transforming growth factor-β (TGF-β): a cytokine that is a master regulator of fibrogenesis, inducing HSC activation and ECM gene expression.

References

1. Metabolic reprogramming in liver fibrosis. Cell Metabolism (2024).
2. MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming. Nature Communications (2023).
3. TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019. Cells (2019).
4. Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis. Cell Reports (2019).
5. Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis. Nature Communications (2020).