Valsartan alleviates acetaminophen-induced hepatotoxicity by activating fibroblast growth factor 21 in acute liver injury in mice.

Previous studies have indicated that Valsartan (Val) modulates peroxisome proliferator-activated receptor α (PPARα) expression in the liver; however, its precise roles in liver injury, both pathological and physiological, remain unclear, necessitating further investigation. This study hypothesises that FGF21 mediates Val's hepatoprotective effects in acetaminophen (APAP)-induced acute liver injury. The results demonstrate that fibroblast growth factor 21 (FGF21) is a key mediator of Val-induced hepatoprotection, acting through the activation of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)/ nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant pathway. This finding reveals a previously unrecognised physiological role for Val beyond its established antihypertensive effects. In a murine model of acute liver injury, Val treatment significantly alleviated APAP-induced hepatic necrosis and oxidative stress, leading to improved survival outcomes. However, the hepatoprotective effects of Val were markedly reduced in FGF21 knockdown models and partially restored following FGF21 reconstitution. Notably, Val maintained considerable efficacy after angiotensinIItype1receptor (AT1R) silencing. In contrast, pharmacological inhibition of the PPARα pathway significantly suppressed Val-induced FGF21 activation and its downstream signalling events. Mechanistically, Val increases hepatic FGF21 expression, which activates the PGC-1α/Nrf2 pathway to counter oxidative damage. In conclusion, these findings position FGF21 as a key mediator of Val-induced hepatoprotection, supporting its repositioning for acute liver injury and expanding Val's clinical applications beyond hypertension to liver-related conditions.