Stevioside promotes hepatocyte proliferation via YAP signaling in cholestatic disease.

Stevioside, a natural glycoside with diverse bioactivities, holds therapeutic potential in liver diseases, but its role in cholestatic liver repair remains largely unexplored. This study investigates the regenerative efficacy and underlying mechanisms of stevioside in bile duct ligation (BDL)-induced cholestatic liver injury. A combined pre- and post-treatment regimen of stevioside (90 mg/kg) robustly mitigated hepatic damage, evidenced by reduced necrosis, suppressed inflammation, attenuated ductular reaction, and improved hepatic function. Notably, stevioside significantly stimulated hepatocyte proliferation, as indicated by increased liver-to-body weight ratios, upregulation of cell-cycle regulators (Ccnd1, Ccna2), and transcriptomic enrichment of proliferation-related pathways. Utilizing the genetic proliferation tracing system (ProTracer), we further demonstrated that stevioside preferentially promotes the regeneration of periportal (Zone 1) and midzonal (Zone 2) hepatocytes. Conversely, it constrained the expansion of biliary epithelial cells and immune cells, thereby collectively alleviating pathological ductular reaction and inflammatory infiltration. Mechanistically, stevioside activated YAP signaling in hepatocytes and remodeled bile acid metabolism, together creating a favorable microenvironment for liver regeneration. Furthermore, stevioside exhibited a favorable safety profile with no detectable hepatotoxicity, fibrosis, or tumorigenic risk under the experimental conditions. Our findings establish that stevioside repairs cholestatic injury by directly driving region-restricted hepatocyte proliferation via YAP signaling, highlighting its potential as a mechanistically innovative candidate for the treatment of cholestatic liver diseases.