SUMOylation and deSUMOylation in sepsis-associated organ injury: cellular mechanisms and translational challenges

Small ubiquitin-like modifier (SUMO) conjugation (SUMOylation) and deconjugation (deSUMOylation) regulate protein stability, subcellular localisation, and protein interactions, but their contributions to organ injury in sepsis remain incompletely understood. This review assesses SUMO-related evidence according to disease relevance and mechanistic causality, distinguishing findings from patient samples and infection-based sepsis models from those obtained in endotoxemia, acute injury models, and other nonsepsis systems. Available evidence implicates SUMOylation and deSUMOylation in inflammatory signalling, immunometabolic adaptation, barrier homeostasis, mitochondrial quality control, and regulated cell death, suggesting potential links between immune dysfunction, cellular stress, and organ injury. Their effects depend on the SUMO paralogue, regulatory enzyme, substrate, modification site, cell type, tissue compartment, and infection context. Changes in bulk SUMO1 or SUMO2/3 conjugation therefore cannot be interpreted as uniformly protective or pathogenic. Direct human evidence and causal evidence resolved by cell type in infection-based models remain limited, and many proposed mechanisms lack endogenous site mapping or rescue validation. Broad pharmacological inhibition of the SUMO pathway has produced discordant results across experimental models, and the clinical safety and efficacy of interventions targeting SUMO in sepsis remain unestablished. Future studies should establish causal relationships between SUMO enzymes, substrates, and modification sites in defined cell types; develop reproducible pharmacodynamic biomarkers; and evaluate targeted interventions in clinically relevant models after infection is established.