Reactivating hepatic stellate cells senescence via PPARγ-LIFR signaling: a novel strategy to resolve liver fibrosis

Liver fibrosis represents a major unmet clinical challenge, and induction of hepatic stellate cell (HSCs) senescence has emerged as a promising therapeutic strategy to halt or reverse fibrotic progression. PPARγ is a key regulator of HSCs quiescence; however, the downstream molecular mechanisms mediating its pro-senescence effects remain poorly defined. Here, we demonstrate that PPARγ expression is markedly reduced in a CCl₄-induced mouse liver fibrosis model and that its restoration drives HSC inactivation and senescence. Through integrated bioinformatics analysis and functional validation in PPARγ-overexpressing HSC-T6 cells, we identified leukemia inhibitory factor receptor (LIFR) as a direct transcriptional target of PPARγ. Mechanistically, PPARγ upregulates LIFR to suppress STAT3 phosphorylation, thereby downregulating fibrosis markers CO Ⅰ and α-SMA, elevating P21 and γ-H2A.X, and reducing CCND1. Crucially, LIFR knockdown abolished all PPARγ-mediated effects, confirming its indispensable role in this axis. Furthermore, combined treatment with the STAT3 inhibitor WP1066 synergistically enhanced PPARγ-driven HSC senescence in a LIFR-dependent manner. These findings establish a PPARγ-LIFR-STAT3 signaling cascade as a critical regulator of HSCs fate, and suggest that pharmacological activation of this axis represents a tractable approach for fibrosis resolution.