Ipragliflozin Exerts Anti-Fibrotic Effects via a Novel Multi-Pathway Mechanism: Targeting TLR4/NF-κB /TGF-β1 Cascade.

Hepatic fibrogenesis represents a significant and escalating global health challenge with few effective treatments. This research explored the anti-fibrotic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitor Ipragliflozin (IPRA) in a rat model of hepatic fibrogenesis caused by thioacetamide (TAA), with a specific focus on critical pathways of inflammation, fibrosis, and oxidative stress. Groups were designated as follows: a control; a model group receiving TAA (100mg/kg, twice weekly for 6 weeks); and two therapeutic groups receiving TAA plus either a low (3mg/kg/day) or high (6mg/kg/day) oral dose of Ipragliflozin during the final 4 weeks. TAA administration induced severe liver fibrosis, characterized by significant increases in serum ALT, AST, triglycerides, cholesterol, oxidative stress (↓GSH, ↓CAT, ↑MDA), and pro-inflammatory/pro-fibrotic signaling (↑TLR4, ↑IL-1β, ↑NF-κB, ↑TGF-β1). Ipragliflozin treatment, particularly at the 6mg/kg dose, dose-dependently and significantly attenuated these changes. It restored liver function, normalized the lipid profile, reversed oxidative stress by boosting antioxidant defenses, and suppressed the core inflammatory and profibrotic TLR4/IL-1β/TGF-β1/NF-κB axis. Histopathological and immunohistochemical findings confirmed a reduction in fibrosis and inflammation. These findings highlight Ipragliflozin's promise as a multi-faceted therapeutic agent for liver fibrosis.