Lactate metabolism and protein lactylation in programmed cell death: From novel mechanism to therapeutic strategies in human diseases

Abstract Protein lactylation is a recently identified post‐translational modification that reflects cellular metabolic status. It plays an important role in regulating gene expression and maintaining essential cellular functions. Dysregulation of lactylation has been implicated in the onset and progression of various human diseases. Programmed cell death (PCD) is a fundamental biological mechanism that determines cellular fate in response to internal and external stress. Although lactylation and PCD were initially regarded as distinct biological processes, recent studies have demonstrated that lactylation directly influences key transcriptional and signaling pathways involved in multiple PCD modalities, thereby reshaping cell‐death regulatory networks under pathological conditions. Nevertheless, the role of lactylation in regulating different forms of PCD across human diseases has not been fully clarified. In this review, we summarize emerging advances that reveal how histone and non‐histone lactylation modulate major PCD pathways and delineate the molecular mechanisms underlying lactylation‐mediated control of cell death programs. Moreover, we discuss the potential of lactylation‐related regulators to serve as promising biomarkers for disease prediction and as attractive targets for therapeutic intervention. Existing studies highlight that lactylation reshapes PCD regulatory circuits under pathological conditions. Lactylation‑associated molecules exhibit great potential as candidate biomarkers for disease prediction and actionable targets for therapeutic intervention. Overall, this review deepens our understanding of how protein lactylation influences programmed cell death and offers new insights into exploiting lactylation‐dependent mechanisms for targeted therapeutic development. Key points Protein lactylation emerges as a key metabolic–epigenetic regulator linking lactate metabolism to programmed cell death. Histone and non‐histone lactylation orchestrate apoptosis, pyroptosis, ferroptosis and autophagy across diverse diseases. Targeting lactylation‐related pathways provides promising opportunities for disease biomarkers and therapeutic intervention.