Naja atra venom induces severe myotoxicity and inflammation largely driven by snake venom phospholipase A2 (SVPLA2). Although the SVPLA2 inhibitor varespladib shows great therapeutic promise, the underlying molecular mechanisms remain unclear. Herein, we uncover dual pathogenic pathways. First, a translational module in which RPL35A interacts with PTBP1 to selectively enhance IL-6 and TNF-α translation without altering mRNA levels. Second, a transcriptional axis where prostaglandin E2-activated p38 MAPK enhances NF-κB signaling and reactive oxygen species production, forming an inflammatory-oxidative cycle. Notably, AAV9-mediated RPL35A knockdown in the mouse gastrocnemius reduces inflammation and tissue injury, with combined p38 inhibition providing synergistic protection in vivo, and similar effects are observed in vitro. Taken together, this study reveals that SVPLA2 drives pathology via coordinated transcriptional and translational mechanisms, supports varespladib's therapeutic potential, and unveils a non-canonical pro-inflammatory role of RPL35A beyond its ribosomal function, which offers therapeutic possibilities for the treatment of other inflammatory diseases.
Liu et al. (Fri,) studied this question.