Lactylation at the crossroads: Bridging metabolic rewiring and ferroptotic vulnerability in cancer

作者：Liu Y, Yang Q, Wang X, Zhao H · 发表于：Redox biology · 年份：2026 · DOI：10.1016/j.redox.2026.104341 · 研究领域：Epigenetic remodeling、Ferroptosis、Histone lactylation、Metabolic vulnerability、Tumor microenvironment、Warburg effect

Metabolic reprogramming and the evasion of regulated cell death are two canonical hallmarks of cancer, yet the mechanistic threads connecting these distinct biological phenomena remain incompletely understood. The "Warburg effect," characterized by robust aerobic glycolysis, results in the massive accumulation of lactate. Once dismissed as a metabolic waste product, lactate has recently emerged as a pivotal signaling molecule and an epigenetic precursor for lysine lactylation (Kla), a novel post-translational modification that fundamentally reshapes the chromatin landscape. Concurrently, ferroptosis-an iron-dependent form of non-apoptotic cell death driven by unrestrained lipid peroxidation-has garnered intense interest as a therapeutic vulnerability in therapy-resistant tumors. However, a paradoxical observation persists highly glycolytic tumors, despite generating abundant ROS (reactive oxygen species), often display intrinsic resistance to ferroptosis. In this review, we propose that histone and non-histone lactylation serves as the critical "epigenetic bridge" coupling metabolic flux to ferroptosis evasion. We dissect the molecular machinery by which the "Lactate-Kla axis" transcriptionally activates antioxidant defenses (e.g., GPX4, SLC7A11) and remodels the tumor microenvironment to suppress ferroptotic triggers. Furthermore, we delineate how targeting the writers and erasers of lactylation can dismantle this metabolic shield, offering a rational strategy to re-sensitiz...