Succinylated-proteome analysis reveals host cellular pathways perturbed by monkeypox virus infection for antiviral targets

Monkeypox virus (MPXV) is a zoonotic pathogen that poses an increasing global public health threat, yet its molecular characterization remains limited despite its clinical relevance. In this study, we conducted a comprehensive proteomic analysis to systematically delineate the dynamic protein expression and succinylation modifications associated with MPXV infection. Our results revealed a significant increase in succinylation of both host and viral proteins post-infection. Integration with MPXV-host interactome profiling uncovered enhanced inflammatory signaling responses alongside the suppression of AKT pathway activity, while AKT overexpression was found to inhibit viral replication. Notably, MPXV infection disrupted metabolic homeostasis by inducing aberrant succinylation of critical enzymes involved in the TCA cycle and carbon/fatty acid metabolism. We further elucidated the mechanism by which the viral protein OPG149 reduces DLAT mRNA levels, a pivotal component of the pyruvate dehydrogenase complex (PDC), leading to hyper-succinylation of cellular proteins. Importantly, both DLAT overexpression and pharmacological inhibition of succinylation demonstrated significant antiviral effects. Collectively, our findings provide insights into the molecular mechanisms by which MPXV manipulates host cellular pathways, enhancing our understanding of its pathogenesis and paving the way for novel therapeutic strategies against MPXV infection.