Investigating the Hepatoprotective Properties of Entresto in Hepatic Ischemia-Reperfusion Injury in Rats: The...

Hepatic ischemia/reperfusion injury (IRI) is a major complication during liver surgery, transplantation, and trauma. This study investigated the potential hepatoprotective effects of Entresto (sacubitril/valsartan), a dual angiotensin receptor-neprilysin inhibitor, in a rat model of hepatic IRI. Male Wistar rats were pretreated with Entresto before 30 min of partial hepatic ischemia followed by 2 h of reperfusion. Serum liver enzymes (ALT, AST), oxidative stress markers (GSH, GSSG, GSH/GSSG ratio, MDA), and liver histopathology were assessed. Antioxidant and signaling proteins (CAT, SOD, GPx-1, PPAR-γ, HO-1, Nrf2, IRAK-M, GCL, NQO1) were determined by ELISA. qRT-PCR assessed HO-1, GCL, NQO1, GPx-1, IL-1β, IL-6, TNF-α, BAX, and BCL-2 mRNA expression, while Western blot analysis analyzed TLR4, MyD88, and NF-κB p65 protein expression. Entresto significantly reduced serum ALT and AST, MDA, and GSSG levels, while increasing GSH and restoring the GSH/GSSG ratio. Histopathology revealed notable restoration of the hepatic architecture. Entresto downregulated proinflammatory cytokines and apoptotic markers (BAX, caspase-3), while upregulating antioxidant and antiapoptotic markers (PPAR-γ, HO-1, Nrf2, BCL-2). Additionally, key proteins in the TLR4/MyD88/NF-κB inflammatory pathway were significantly suppressed. These findings suggest that Entresto confers hepatoprotection against IRI by reducing oxidative stress, inflammation, and apoptosis, likely via modulation of TLR4/MyD88/NF-κB and PPAR-γ/Nrf2/HO-1 signaling pathways.