The context-dependent bidirectional regulation of lactylation in hypoxia-driven pathologies: A tripartite framework

Lysine lactylation (Kla) has emerged as a definitive mechanistic bridge coupling cellular metabolic flux to epigenetic and proteomic reprogramming. Driven by hypoxia-induced lactate accumulation, this dynamic post-translational modification fundamentally shapes chromatin architecture and the functions of non-histone proteins. However, current literature frequently mischaracterizes lactylation as a uniform pathogenic driver, overlooking its essential roles in maintaining homeostasis and tissue repair. To address this limited understanding, we propose a refined tripartite framework: the bidirectional functional outcomes of lactylation are tightly regulated by cell-type specificity, temporal dynamics, and concentrationdependence. By mapping this framework across the tumor microenvironment and systemic pathologies-including cardiovascular, respiratory, renal, and neurological disorders-we delineate how identical lactate pools can execute diametrically opposed epigenetic programs. Furthermore, we critically evaluate the enzymatic machinery-including p300/CREB-binding protein (CBP), histone deacetylases (HDACs), and sirtuins (SIRTs)-and expose the "specificity paradox" and sub-stoichiometric limitations confounding current translational efforts. Ultimately, we argue that future clinical interventions must pivot from the indiscriminate systemic ablation of glycolysis toward the precise spatiotemporal titration of lactylation targets, providing a robust molecular blueprint for next-generation metabolic-epigenetic therapies.