S-palmitoylation at the interface between lipophagy and macrophage immunometabolism in sepsis: mechanistic evidence and translational questions.

Sepsis seldom presents as a uniform immune phenotype. Inflammation and immune suppression often overlap, but their balance shifts across patients, organs, and illness stages. Macrophages sit within this variation, coordinating cytokine output, microbial clearance, antigen processing, and presentation. Lipophagy removes lipid droplets through selective autophagy. The released fatty acids can feed mitochondrial β-oxidation, helping macrophages balance lipid storage with energy demand. Reduced flux may instead leave excess droplets, compromise mitochondrial function, and blunt antimicrobial activity. Whether this sequence directly drives sepsis-associated immunoparalysis remains uncertain. Protein S-palmitoylation offers a second potential control point through reversible cysteine S-acylation. Studies have linked this modification to ATG16L1 and ATG4B, and to immune regulators including MYD88, NLRP3, and CD80. Most of that evidence, however, comes from models other than sepsis, so its relevance cannot be assumed. This review therefore examines the proposed links among macrophage lipophagy, immunometabolic failure, and sepsis-associated immunoparalysis while keeping experimentally established observations separate from mechanistic inference. Taken together, current findings support S-palmitoylation as a plausible regulatory layer, but they do not establish an integrated causal axis linking S-palmitoylation, lipophagy, and immunometabolism in sepsis. This framework awaits direct testing in primary macrophages, organ-specific sepsis models, and longitudinal clinical cohorts.