Autophagy-Related Mechanisms in Hepatic Fibrosis

Hepatic fibrosis, a reversible wound‐healing response to chronic liver injury, is driven principally by the activation of hepatic stellate cells (HSCs) and excessive deposition of extracellular matrix (ECM). Autophagy, an evolutionarily conserved pathway for lysosomal degradation and recycling of intracellular components, has emerged as a pivotal regulator of both the initiation and resolution phases of fibrosis. In quiescent HSCs, basal autophagy maintains lipid droplet turnover and cellular homeostasis, whereas upon chronic insult autophagic flux is upregulated, supplying energy and substrates that facilitate transdifferentiation into collagen‐secreting myofibroblasts. Conversely, selective modulation of autophagy in hepatocytes and Kupffer cells can confer cytoprotection, mitigate inflammation and promote scar degradation by matrix‐degrading enzymes. A fine balance between bulk autophagy, mitophagy (the selective clearance of damaged mitochondria) and autophagic flux underpins the crosstalk between parenchymal cells and non‐parenchymal effector populations, underscoring the global significance of autophagy‐targeted strategies for anti‐fibrotic therapy.

Research from Nature Portfolio

Recent investigations have shed light on the lipid‐droplet‐associated protein ATG2A as a critical nexus between autophagy and HSC activation. In human and murine models, enlargement of lipid droplets by retinol or oleic acid was found to reverse the activated phenotype of HSCs, an effect accompanied by enrichment of ATG2A within the droplet proteome. Loss of ATG2A reduced autophagic flux, enlarged lipid stores and suppressed activation markers such as α‐smooth muscle actin, whereas ATG2A deficiency also impaired autophagosome formation. These findings indicate that modulation of lipid‐droplet dynamics via ATG2A offers a novel entry point for inhibiting HSC activation and arresting fibrogenesis.

Autophagy-Related Mechanisms in Hepatic Fibrosis publication trend

The graph below shows the total number of articles in autophagy-related mechanisms in hepatic fibrosis across all publications each year (not limited to Nature Index journals).

Technical terms

Autophagy: A cellular degradation process in which cytoplasmic cargo is sequestered in autophagosomes and delivered to lysosomes for recycling.

Autophagic flux: The dynamic sequence of autophagosome formation, maturation and lysosomal degradation reflecting pathway activity.

Hepatic stellate cell (HSC): A vitamin A–storing perisinusoidal liver cell that, upon activation, adopts a myofibroblast‐like phenotype and produces extracellular matrix.

Extracellular matrix (ECM): The network of collagens, glycoproteins and proteoglycans that provides structural support to tissues.

Mitophagy: The selective autophagic removal of damaged or superfluous mitochondria to maintain organelle quality control.

References

1. Programmed cell death in hepatic fibrosis: current and perspectives. Cell Death Discovery (2023).
2. Machine learning and experimental validation identified autophagy signature in hepatic fibrosis. Frontiers in Immunology (2024).
3. Autophagy: A Multifaceted Partner in Liver Fibrosis. BioMed Research International (2014).
4. In vitro inhibition of hepatic stellate cell activation by the autophagy-related lipid droplet protein ATG2A. Scientific Reports (2018).