Background and Aims: Hepatic stellate cell (HSC) activation is central to liver fibrosis, but emerging evidence suggests HSC homeostatic activity. We compared HSC functions in parenchymal injury (CCl₄-driven) versus metabolic dysfunction-associated steatohepatitis (MASH; choline deficient high fat diet, CD-HFD) and identify therapeutic targets preserving HSC homeostatic functions. Approach and Results: Inducible HSC ablation was performed in Lrat-iDTR mice during active fibrogenesis. Multi-parametric analyses were conducted to assess roles of HSCs in two established fibrosis models, with a focus on elucidating the cellular origins of myofibroblasts and the alterations in regeneration and ductular reaction. RNA-seq from human biopsies validated mechanisms. HSC depletion in the CD-HFD model not only exacerbated MASH but also elevated a-SMA + myofibroblasts derived from PDGFRα⁺ portal fibroblasts, impaired hepatocyte function (metabolic zonation and regeneration), and enhanced the ductular reaction. Conversely, HSC depletion in the CCl₄ model attenuated fibrosis without affecting hepatic regeneration or metabolic zonation. Strikingly, 85.5% of quiescent HSCs-enriched genes remained upregulated in MASH-associated HSCs, unlike in CCl 4 fibrosis. RNA-seq followed by in vivo studies identified extracellular matrix protein 1 (ECM1), as a master regulator of HSC quiescence, and HSC-specific ECM1 overexpression suppressed CCl₄-induced fibrosis. In human biopsies (MASH, HBV, PBC, PSC), ECM1 expression inversely correlated with fibrosis stage. Conclusions: HSCs exhibit dual roles contingent on disease context: in MASH with moderate inflammation, they maintain homeostasis, whereas in massive CCl₄-driven injury, activated HSCs promote fibrogenesis. ECM1 enforces HSC quiescence and facilitates fibrosis resolution. Antifibrotic therapies based on general HSC ablation may be harmful.
Yang et al. (Thu,) studied this question.