Historically, lactate has been regarded primarily as the terminal product of glycolysis. However, recent research has elucidated its critical function as an epigenetic regulator via lactylation modification. Lactylation represents a novel post-translational modification (PTM) characterized by the covalent attachment of lactyl groups to lysine residues on both histone and non-histone proteins. This modification influences protein function at transcriptional and post-translational stages, thereby forging a direct connection between lactate metabolism and epigenetic regulation. Lytic cell death (LCD) encompasses a group of inflammatory programmed cell death modalities characterized by the rupture of the plasma membrane, playing a pivotal role in the pathogenesis of various diseases. This review provides a comprehensive synthesis of recent advancements in understanding the regulatory axis between L-lactate-induced lysine lactylation (KL-la) and LCD in disease contexts. Emerging evidence suggests that KL-la modulates several LCD subtypes, including pyroptosis, ferroptosis, and NETosis, thereby influencing disease progression and clinical outcomes. Notably, the regulatory effects of KL-la are highly context-dependent. Within the tumor microenvironment, KL-la primarily inhibits LCD, thereby promoting tumor cell survival. Conversely, in non-tumor conditions such as inflammation and ischemic injury, KL-la frequently enhances LCD, leading to increased tissue damage. This review also underscores therapeutic strategies that target lactate metabolism and KL-la-related enzymes to modulate LCD. Future interventions must incorporate the pathological context, cell-type specificity, and molecular targets. The advancement of context-responsive precision strategies, such as microenvironment-activated prodrugs or cell-specific delivery systems, will be crucial for the realization of safe and effective targeted therapies.
Zhang et al. (2026) studied this question.