Targeting Lactylation Offers Therapy to Reverse Cell Death Resistance

Lactylation, a lactate-derived post-translational modification, emerges as a master metabolic regulator of resistance to regulated cell death (RCD) across pathologies including cancer, inflammatory disorders, and degenerative diseases. By dynamically modifying histones and non-histone proteins via lactyltransferases and delactylases, lactylation orchestrates convergent molecular pathways that suppress ferroptosis, cuproptosis, and apoptosis. This review synthesizes current understanding of lactylation as a central regulator of RCD resistance in diseases, especially in cancers. We dissect the molecular machinery through which lactylation subverts ferroptosis, cuproptosis, and apoptosis; evaluate its pathophysiological implications in diverse pathologies; and discuss emerging therapeutic strategies to disrupt lactylation-mediated cell death evasion. This metabolic-epigenetic crosstalk establishes a robust shield against RCD in disease microenvironments, promoting therapeutic resistance and pathological resilience. Targeting lactylation regulators (writers/erasers) or combining lactate modulation with RCD inducers represents a promising strategy to overcome treatment-refractory conditions in cancers.