TARGETING THE LACTYLATION-PYROPTOSIS AXIS IN CHRONIC WOUNDS: AN IMMUNOMETABOLIC FRAMEWORK FOR PHYTOCHEMICAL NANOTHERAPEUTICS

Abstract

Chronic wounds represent a considerable clinical burden associated with prolonged inflammation, metabolic dysregulation, and impaired tissue regeneration. The role of metabolic reprogramming in the maintenance of non healing wound environments is being underscored by emerging evidence from immunometabolism. In that regard, the lactylation–pyroptosis axis has been examined as a novel mechanism that integrates hypoxia-driven glycolysis, lactate accumulation, epigenetic regulation, and inflammasome-mediated inflammatory cell death. Histone lactylation serves as a metabolic–epigenetic interface, supporting lactate-derived chromatin modifications relevant to regulating immune modulation and tissue repair genes. On the contrary, pyroptosis enhances inflammation through NLRP3 inflammasome activation, caspase-1–mediated cleavage of gasdermin D, and secretion of pro-inflammatory cytokines including interleukin-1β and interleukin-18. This axis dysregulation contributes toward sustained inflammation, defective macrophage polarization, and delayed wound healing. This review offers a summary overview of the immunometabolic profile of chronic wounds, highlighting the interactions between lactylation and pyroptotic mechanisms. It continues to discuss the therapeutic effect of phytochemicals as active multifunctional modulators modulating metabolism and inflammation. This review presents the use of phytochemicals into nanocarrier systems (nanocarriers) as a novel approach for improving stability, bioavailability, targeted delivery, and controlled release in the wound microenvironment. While promising preclinical data, translational hurdles include incomplete mechanistic insights, few biomarkers, and nanotherapeutics scalability challenges. Targeting the lactylation–pyroptosis axis represents an exciting avenue for the development of next-generation therapies in chronic wound treatment.