Telmisartan targets Nrf2-HO1 axis in MASLD modulating oxidative stress, inflammation, and mitochondrial dysfunction:...

Metabolically dysfunction-associated steatotic liver disease (MASLD) has emerged as the leading chronic liver disease worldwide, driven primarily by metabolic derangement. The current investigation proposes to elucidate the hepatoprotective mechanisms of telmisartan (TEL) in MASLD. Twenty-four male Wistar rats were allocated to four groups (Control, MASLD, TEL-treated, and MASLD/TEL). Lipid profiles, glycemic markers, liver enzymes, and hepatic markers of oxidative stress (malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and catalase) were measured. MASLD-associated genes retrieved from GeneCards® were mapped to Rattus norvegicus ortholog genes using the gprofiler2 R package. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome enrichment analyses were subsequently performed using the clusterProfiler R package. Hepatic inflammatory cytokines (TNF-β, IL-6, and NF-κB), mitochondrial respiratory enzymes (Complexes I-IV), and the gene expression of Nrf2, HO-1, MMP-9, and TIMP-1 were evaluated using spectrophotometric assays for mitochondrial respiratory enzymes. Histological assessment was done using Hematoxylin and Eosin (H&E) staining, Masson's trichrome, and TGF-β immunostaining. TEL ameliorates MASLD-associated disturbances in the serum ALT level and lipid profile. It significantly reduces the levels of oxidative stress markers. KEGG and Reactome enrichment highlighted pathways involved in lipid metabolism, insulin resistance, and inflammation, with the peroxisome proliferator-activated receptor (PPAR) and AMP-activated protein kinase (AMPK) signaling pathways being the most enriched. TEL treatment increased the hepatic expression of Nrf2, HO-1, and TIMP-1 while decreasing the expression of MMP-9. The levels of the proinflammatory cytokines TNF-α and IL-6 decreased. The activities of mitochondrial enzymes (citrate synthase and complex I) improved. MASLD induced marked hepatic fibrosis, which was markedly improved following TEL treatment. TEL has notable hepatoprotective properties in MASLD by enhancing metabolic parameters, decreasing oxidative stress, and moderating inflammatory reactions.