Varespladib attenuates <i>Naja atra</i> -induced acute liver injury via reversing Nrf2 signaling-mediated ferroptosis and mitochondrial dysfunction
Jiahao Liu, Linfeng Wang, Mengxia Xie, Wenjie Zhao, Jiaqi Sun, Yuji Jin, Meiling Liu, Jianqi Zhao, Lixia Cheng, Cheng Wen, Xiaowen Bi, Chunhong Huang
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.