Lhx2 specifically expressed in HSCs promotes liver regeneration and inhibits liver fibrosis

Background and Aims: Promoting liver regeneration while inhibiting fibrogenesis represented an attractive strategy for treating liver diseases, with HSCs being crucial to both processes. This study aimed to identify specific targets in HSCs that simultaneously facilitated regeneration and suppressed fibrosis, and elucidated their molecular mechanisms. Approach and Results: Through comparing acute and chronic liver injury mouse models induced by CCl 4 injections, we revealed that HSCs exhibited dual functionality, expressing pro-regenerative and profibrogenic genes following injury. Analyzing RNA-seq data from primary HSCs of these models, along with publicly available single-cell RNA-seq data of HSCs, we identified transcription factor Lhx2, specifically expressed in HSCs, as a potential regulator of the dual functions. Notably, Lhx2 showed significantly higher expression in HSCs from healthy liver tissue compared to fibrotic liver, in both mouse and human models. Lhx2 knockdown impaired liver function recovery and cellular proliferation after acute liver injury. Consistent changes were observed in mice with HSC-specific Lhx2 overexpression. In addition, Lhx2 overexpression not only promoted hepatocyte proliferation but also exhibited an antifibrogenic function after chronic injury. Mechanistically, Lhx2 suppressed multiple functions of activated HSCs, including fibrogenesis, proliferation, and migration, and upregulated SMAD6 to block the TGF-β signaling pathway. Moreover, Lhx2 was an upstream regulator of various pro-regenerative factors, especially HGF, which is crucial for liver regeneration. Conclusions: We demonstrated that Lhx2 had pro-regenerative and antifibrogenic functions, and elucidated its regulatory mechanism. The study provided a potential target with dual effects for treating liver diseases.