What question did this study set out to answer?

This research aims to elucidate the molecular mechanisms by which the Chinese cobra toxin induces muscle inflammation.

April 20, 2026Open Access

Chinese cobra (Naja atra) SVPLA2 promotes muscle inflammation via RPL35A-mediated translational reprogramming

Key Points

This research aims to elucidate the molecular mechanisms by which the Chinese cobra toxin induces muscle inflammation.
Identified translational module involving RPL35A and PTBP1 to enhance IL-6 and TNF-α translation.
Examined transcriptional activation of p38 MAPK and NF-κB signaling.
Utilized AAV9-mediated RPL35A knockdown in mice to assess inflammation and tissue injury.
Conducted in vitro analyses to confirm in vivo findings.
Evaluated combined p38 inhibition effects.
RPL35A selectively enhances IL-6 and TNF-α translation without changing mRNA levels.
p38 MAPK activation leads to increased NF-κB signaling and reactive oxygen species production.
Knockdown of RPL35A in mice results in reduced muscle inflammation and tissue injury.
Synergistic protective effects observed with combined p38 inhibition in vivo and in vitro.

Abstract

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.

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