Lactate and lactylation in sepsis: regulation of immune-metabolic crosstalk and organ injury.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and remains a leading cause of death worldwide. Hyperlactatemia, a hallmark metabolic disorder in sepsis, has recently been recognized as an epigenetic modulator via lysine lactylation. This Review synthesizes the evolving understanding of lactate-from a prognostic biomarker to a pathogenic mediator and, most recently, to an epigenetic modulator through lysine lactylation (Kla). Sepsis induces persistent Warburg-like glycolytic reprogramming in immune and parenchymal cells, generating lactate that not only serves as a metabolic fuel but also accumulates to drive covalent histone and non-histone Kla. Rather than merely indicating tissue hypoxia, this lactate surge directly remodels transcriptional and metabolic programs via both lactyl-CoA-dependent (p300/CBP, KAT2B) and lactyl-CoA-independent (AARS1/2) lactylation pathways. We dissect the emerging regulatory network of Kla in sepsis, including validated "writers" and "erasers", as well as potential writers and erasers awaiting validation in sepsis models, and map their cell type-specific and substrate-specific effects on acute lung injury, cardiomyopathy, acute kidney injury, and vascular dysfunction. The identical lactylation mark-exemplified by H3K18la-exhibits a context-dependent duality, being protective in macrophages yet pathogenic in alveolar or tubular epithelia. This complexity underscores the urgent need for precision-oriented therapeutic strategies. We further explore how lactate and Kla shape the immunopathological landscape of sepsis by modulating macrophage polarization, trained immunity, neutrophil extracellular trap (NET) formation, and T-cell dysfunction, and we compare these effects with the relatively more uniform immunosuppressive role of lactylation in cancer. Finally, we map the currently known landscape of both histone and non-histone Kla across the various stages of sepsis, thereby providing new avenues for mechanism-based therapies in sepsis and other inflammation-associated disorders.