ECM1 produced by hepatic stellate cells serves as gate keeper of liver homeostasis in hepatic fibrosis

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.