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Description

Succinic acid, a naturally occurring metabolic intermediate and widely used dietary supplement, is emerging as a powerful dual-action inhibitor with significant therapeutic promise. This work reveals that succinic acid effectively suppresses the activity of phospholipase A₂ (PLA₂) and key proteases, enzymes that play central roles in inflammation, pain, tissue damage, and disease progression. PLA₂ enzymes, prevalent in mammalian systems and animal venoms, initiate inflammatory cascades through arachidonic acid release, making their inhibition a long-standing goal in drug discovery and venom therapy. Through a combination of biochemical assays, isothermal titration calorimetry, structural biology, and molecular modeling, this study elucidates the molecular basis of succinic acid’s inhibitory activity. High-resolution crystallographic analysis of succinic acid bound to trypsin reveals direct interactions with the catalytic triad, while binding studies confirm strong and energetically favorable inhibition. Complementary docking and simulation analyses further demonstrate its ability to target both serine and cysteine proteases, including trypsin and papain. Collectively, these findings position succinic acid as a versatile, naturally derived inhibitor with broad therapeutic relevance. Its dual action against PLA₂ and proteases, together with previously reported antiviral properties, underscores its potential application in the management of inflammatory disorders, venom-induced toxicity, and infectious diseases, offering a compelling example of how simple metabolites can yield complex biomedical benefits.