Integrated network pharmacology and in vivo experimental approaches unveil the modulatory effect of telmisartan on autophagy in a rat model of nonalcoholic steatohepatitis

Abstract

Defective autophagy contributes to the progression of various diseases, including nonalcoholic steatohepatitis (NASH). While telmisartan's hepatoprotective effects are well established, its impact on hepatic autophagy in NASH remains unclear. This study employed network pharmacology combined with in vivo experiments to predict and validate telmisartan's effects on hepatic autophagy in a rat model of NASH. Additionally, we investigated whether telmisartan could augment pioglitazone's protective effects.

Network pharmacology identified 97 common molecular targets shared by telmisartan and NASH. Key targets included Signal Transducer and Activator of Transcription 3 (STAT3), B-cell lymphoma 2 (Bcl2), and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), regulators of cellular autophagy, suggesting telmisartan's potential interaction with autophagy-related pathways. To validate these findings, NASH was induced in adult male rats via an 18-week high fructose, fat, and salt diet, with telmisartan, pioglitazone, or their combination administered orally during the final 10 weeks. Blood pressure, glycemic, lipid, and liver function parameters were quantified in serum. Besides, hepatic markers of autophagy (Beclin1, LC3, and p62), inflammation, oxidative stress, fibrosis, and apoptosis were measured. Moreover, liver histology and collagen deposition were examined.

Telmisartan significantly enhanced hepatic autophagy more than pioglitazone. Furthermore, combination therapy synergistically increased autophagy beyond the effects of either drug alone. Both drugs similarly ameliorated hepatic inflammation and oxidative stress markers. These results demonstrate that telmisartan's hepatoprotective effects are partly mediated by restoration of hepatic autophagy. Moreover, the data suggest that combined telmisartan and pioglitazone therapy may provide enhanced benefit in NASH treatment, warranting further clinical investigation.