Protein Lactylation Modulating Regulated Cell Death: A Novel Therapeutic Target in Neurological Diseases

Dysregulation of regulated cell death (RCD), including ferroptosis, pyroptosis, autophagy, and others, has been shown to contribute to the development of neurological diseases. Accumulating studies indicate that protein lactylation, a newly discovered posttranslational modification (PTM) of lysine residues on histone and nonhistone proteins, modulates these forms of RCD and contributes to the pathogenesis of neurological diseases. Here, we summarize the core molecular mechanisms of protein lactylation, followed by a detailed description of the roles of protein lactylation regulation in RCD during the genesis of neurological diseases, including cerebrovascular diseases (CVDs), neurodegenerative diseases (NDDs), spinal cord injury (SCI), and traumatic brain injury (TBI), among others. This review uniquely synthesizes emerging evidence to establish a novel mechanistic link between metabolic reprogramming, epigenetic regulation via lactylation, and RCD pathways in neurological contexts-a perspective not yet comprehensively integrated in existing literature. This review also outlines the innovative strategy of targeting protein lactylation with therapeutic compounds-a therapeutic approach for regulating RCD and transforming the landscape of disease treatment. Overall, it highlights a novel strategy for neurological disease therapy by pharmacologically targeting the protein lactylation axis with therapeutic compounds and clarifies how this axis serves as a convergent node bridging metabolic dysfunction with cellular demise in the nervous system.