Varespladib attenuates Naja atra-induced acute liver injury via reversing Nrf2 signaling-mediated ferroptosis and mitochondrial dysfunction.

Objective: To investigate the protective effects of varespladib against Naja atra-induced acute liver injury (ALI) and to elucidate the toxic mechanism of snake venom phospholipase A(2) (SVPLA(2))-induced hepatic oxidative stress, with a particular focus on the role of Nrf2 signaling and its downstream pathways.Methods: A combination of in vivo and in vitro models of N. atra envenomation was employed to assess liver injury, oxidative stress, and mitochondrial dysfunction. The interaction between SVPLA(2) and Nrf2 was analyzed, and the effects of varespladib treatment on these processes were evaluated using histological analysis, biochemical assays, and molecular techniques targeting oxidative stress, ferroptosis, mitophagy, and apoptosis.Results: Varespladib significantly alleviated N. atra-induced ALI. SVPLA(2) was found to directly bind to Nrf2, leading to severe oxidative stress. This oxidative stress initiated a cascade involving Nrf2-mediated ferroptosis, mitochondrial dysfunction, excessive mitophagy, and mitochondria-dependent apoptosis. Treatment with varespladib effectively reversed these pathological events by inhibiting SVPLA(2) activity.Conclusion: Varespladib shows strong therapeutic potential for N. atra envenomation by targeting SVPLA(2). Nrf2 was identified as a direct toxic target of SVPLA(2), and Nrf2-mediated ferroptosis and mitochondrial dysfunction were key mechanisms underlying SVPLA(2)-induced hepatic injury.