Ipragliflozin exerts anti-fibrotic effects via a novel multi-pathway mechanism: Targeting TLR4/NF-κB /TGF-β1 cascade

Area of Science:

• Hepatology
• Pharmacology
• Fibrosis Research

Background:

• Hepatic fibrogenesis is a major global health concern with limited treatment options.
• Thioacetamide (TAA)-induced liver fibrosis in rats is a well-established model for studying anti-fibrotic therapies.

Purpose of the Study:

• To investigate the anti-fibrotic effects of Ipragliflozin (IPRA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor.
• To evaluate IPRA's impact on inflammation, oxidative stress, and fibrosis pathways in a TAA-induced rat liver fibrosis model.

Main Methods:

• Rats were induced with liver fibrosis using TAA (100mg/kg, twice weekly for 6 weeks).
• Therapeutic groups received TAA plus low (3mg/kg/day) or high (6mg/kg/day) doses of Ipragliflozin for the final 4 weeks.
• Assessed liver function markers (ALT, AST), lipid profiles, oxidative stress indicators (GSH, CAT, MDA), and inflammatory/fibrotic signaling pathways (TLR4, IL-1β, NF-κB, TGF-β1).
• Histopathological and immunohistochemical analyses were performed.

Main Results:

• TAA administration significantly increased liver injury markers, dyslipidemia, oxidative stress, and pro-inflammatory/pro-fibrotic signaling.
• Ipragliflozin treatment dose-dependently attenuated these TAA-induced changes.
• High-dose Ipragliflozin significantly restored liver function, normalized lipid profiles, reversed oxidative stress, and suppressed key inflammatory and fibrotic pathways.
• Histology confirmed reduced fibrosis and inflammation.

Conclusions:

• Ipragliflozin demonstrates significant anti-fibrotic, anti-inflammatory, and antioxidant properties in a rat model of liver fibrosis.
• The SGLT2 inhibitor IPRA effectively targets critical pathways involved in hepatic fibrogenesis.
• Ipragliflozin presents a promising multi-faceted therapeutic candidate for liver fibrosis treatment.