Protective anti-fibrotic effect of liraglutide and Pirfenidone combination therapy on liver fibrosis in rats: effects on autophagy and NLRP3 inflammasome.

BACKGROUND: Liver fibrosis is a significant complication of chronic liver diseases. While Pirfenidone (PFD) and Liraglutide (LIR) have shown promise individually in treating fibrosis, their combined effect on autophagy and NLRP3 inflammasome pathways remains largely unexplored. METHODS AND RESULTS: This study investigated the protective effects of combined LIR and PFD therapy on autophagy and NLRP3 inflammasome, fifty male Wistar rats were divided into five groups: Sham, BDL, BDL + PFD (200 mg/kg), BDL + LIR (200 µg/kg), and BDL + PFD + LIR combination. Following 20 days of treatment, liver tissues were analyzed for histological and immunohistochemical (IHC) changes, biochemical parameters, and molecular markers of fibrosis, autophagy, and inflammasome activation. The combination therapy significantly reduced serum liver injury markers (ALT, AST, ALP), decreased ECM deposition, and improved histological parameters compared to monotherapy. Combined treatment effectively suppressed inflammatory markers (NF-κB, TNF-α) while increasing anti-inflammatory IL-10. Furthermore, the combination therapy modulated autophagy markers (Beclin 1), cathepsin B, and reduced NLRP3 inflammasome activation (NLRP3, Caspase 1, IL-1β, IL-18) more effectively than either drug alone. IHC staining of Ki-67 and HepPar-1 showed that combination therapy enhanced expression of proliferative and differentiation markers. CONCLUSIONS: PFD and LIR combination therapy demonstrates superior therapeutic efficacy in treating BDL-induced LF through enhanced liver regeneration through enhanced expression of proliferative and differentiation markers and modulation of autophagy and NLRP3 inflammasome pathways, indicating that the combination of PFD and LIR represents a promising therapeutic strategy for LF.