Caveolin-1 deficiency exacerbates liver fibrosis by driving lipid metabolic reprogramming in hepatic stellate cells via DRP1-mediated mitochondrial fission.

Liver fibrosis represents a prevalent pathological outcome of sustained hepatic injury and is largely driven by aberrant activation of hepatic stellate cells (HSCs). Emerging evidence suggests that mitochondrial dynamics and lipid metabolic remodeling play critical roles in HSC activation; however, the upstream regulatory mechanisms remain incompletely understood. Here, we identify Caveolin-1 (CAV1) as a critical suppressor of HSC activation. CAV1 deficiency enhances DRP1-mediated mitochondrial fission, elevating mitochondrial reactive oxygen species (mtROS) and shifting lipid metabolism toward fatty acid oxidation, thereby fueling HSC activation. Inhibition of DRP1 with Mdivi-1 restored mitochondrial homeostasis, reduced mtROS, normalized lipid metabolism, and suppressed HSC activation. In vivo, CAV1 knockout aggravated CCl4-induced liver fibrosis via DRP1-dependent mitochondrial fission and metabolic reprogramming, while Mdivi-1 treatment alleviated fibrosis. Collectively, these findings identify CAV1 as a critical upstream regulator of HSC activation and liver fibrosis through modulation of DRP1-mediated mitochondrial fission, mtROS generation, and lipid metabolic reprogramming, highlighting a potential therapeutic target for liver fibrosis.