Targeting TXNIP With Saroglitazar Mitigates Acute Hepatic Injury in Rats Challenged With Thioacetamide: A Multistep Computational and Experimental Approach

Abstract

Acute hepatic injury (AHI) is a sudden onset of hepatic inflammation, a key contributor to the progression of diabetes and other disorders. Diabetes mellitus also increases the risk of liver illnesses associated with inflammatory disorders. According to recent studies, Saroglitazar (SAR), originally developed for the treatment of hyperglycemia and dyslipidemia, has also demonstrated notable anti-inflammatory properties. In our search for a prime therapeutic approach for inflammatory liver disorders in diabetic patients, we investigated the effects of SAR on thioacetamide (TAA)-induced AHI in rats. In order to investigate possible interactions between SAR and thioredoxin-interacting protein (TXNIP), this research utilized a multistep methodology that included prediction of computational targets, network analysis, molecular docking, and experimental verification. Findings revealed the anti-inflammatory potential of SAR, presumably ascribed to its inhibition of the NLRP3 signaling pathway by inhibiting TXNIP, an NLRP3 inflammasome upstream regulator. Furthermore, SAR inhibited the priming signal brought on by NFκB stimulation and the succeeding inflammasome components, cleaved caspase-1, GSDMD, IL-1β, and IL-18. As a result, SAR demonstrated anti-pyroptotic properties in the injured liver. Moreover, SAR exhibited potential antiapoptotic effects, as indicated by decreased Bax levels, decreased tissue expression of cleaved caspase-3, and increased BCL2 levels. Improvements in liver function, oxidative stress markers, liver histology, and the liver weight-to-body weight ratio all supported these findings. In conclusion, SAR demonstrates potential as a preventive treatment for inflammatory liver disorders. To render these preclinical findings into efficient techniques for enhancing hepatic function, more research is required, particularly in the context of diabetes.