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SaPLIγ is a novel gamma phospholipase A2 inhibitor (PLI) recently isolated from Sinonatrix annularis, a Chinese endemic non-venomous snake. To explore the neutralization effects of saPLIγ in snakebite envenomation, a dose equivalent to LD50 of Deinagkistrodon acutus, Agkistrodon halys and Naja atra venom with/without saPLIγ was inoculated into the gastrocnemius muscle of female Kunming mice. The ability of saPLIγ to inhibit myonecrosis and systemic toxicity were evaluated through investigations of muscle histopathology, and determination of the serum levels of creatine kinase (CK), lactate dehydrogenase isoenzyme1 (LDH1) and aspartate transferase (AST). Edema of the gastrocnemius muscle was evaluated by calculating the width difference between the inoculated limb and the contralateral leg. Desmin loss in the gastrocnemius muscle was determined by Western blot analysis. Co-immunoprecipitation and shotgun LC-MS/MS analyses were performed to identify venom proteins that interact with saPLIγ. All the envenomed mice had significantly elevated serum CK, LDH1 and AST levels, whereas the levels were decreased significantly in the presence of saPLIγ. Histopathological evaluation of gastrocnemius muscle sections showed severe snake venom-induced damage, characterized by leukocyte infiltration and erythrocyte leakage, leading to local edema. Myonecrosis, hemorrhage and desmin loss were significantly attenuated by saPLIγ. SaPLIγ interacted with a wide range of venom proteins, including PLA2s, metalloproteinases and C type lectins, which may contribute to broad anti-venom effects.SaPLIγ has a wide protection effect to local myonecrosis and systemic toxic reaction against snake venom.Snake envenomation also leads to severe leukocyte infiltration and erythrocyte leakage.Desmin loss in damaged myofiber is relieved in the presence of saPLIγ.SaPLIγ interacts with a number of venom proteins, including PLA2s, metalloproteinases, C type lectins.