Naja atra SVPLA₂ contributes to venom-induced AKI via HRAS palmitoylation-dependent PI3K-AKT inactivation

Clinically, acute kidney injury (AKI) is one of the most frequent complications of Naja atra (N. atra) envenomation, primarily attributed to snake venom phospholipase A₂ (SVPLA₂). Although the SVPLA₂ inhibitor varespladib shows great therapeutic promise, the underlying mechanisms remain incompletely understood. Herein, we integrated multi-omics and molecular biology approaches to investigate the critical role of SVPLA₂ in N. atra venom-induced AKI, as evidenced by pharmacological inhibition with varespladib. Proteomic profiling identified HRAS and CCND1 as key mediators of SVPLA₂-induced nephrotoxicity. Mechanistically, SVPLA₂ disrupts lipid raft integrity, impairing HRAS palmitoylation-dependent plasma membrane localization and GTPase activity. This defect suppresses phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, causing apoptosis and cell cycle arrest in renal tubular epithelial cells, enforced activation of PI3K-AKT signaling effectively rescued cells from injury. Beyond direct cytotoxicity, SVPLA₂ profoundly remodels the renal immune microenvironment. SVPLA₂ enhances glycolysis by upregulating hexokinase 2 (HK2) while suppressing fatty acid oxidation through downregulation of carnitine palmitoyltransferase IA, thereby metabolically driving M1 polarization. This metabolic shift impairs macrophage efferocytosis and sustains inflammatory injury. HK2 knockdown reverses these effects in macrophages. Taken together, this study reveals a dual epithelial-immune mechanism by which SVPLA₂ activity critically contributes to N. atra venom-induced AKI, as evidenced by pharmacological inhibition with varespladib. These findings highlight PI3K-AKT signaling and HK2 as potential therapeutic targets for N. atra-triggered AKI. Supplementary key words.