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

Abstract

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 A₂ (SVPLA₂)-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 SVPLA₂ 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. SVPLA₂ 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 SVPLA₂ activity.Conclusion: Varespladib shows strong therapeutic potential for N. atra envenomation by targeting SVPLA₂. Nrf2 was identified as a direct toxic target of SVPLA₂, and Nrf2-mediated ferroptosis and mitochondrial dysfunction were key mechanisms underlying SVPLA₂-induced hepatic injury.