A comprehensive review recently published in Current Molecular Pharmacology provides a timely and in‑depth analysis of how lactylation—a post‑translational modification driven by lactate—contributes to the progression and treatment resistance of lung cancer. The authors, led by corresponding author Yong Xu from Shanghai Pulmonary Hospital, Tongji University, synthesize emerging evidence that positions lactylation as a critical metabolic‑epigenetic hub linking the Warburg effect to malignant behavior, immune suppression, and therapeutic failure.
The review introduces a conceptual “reflex arc” model comprising writers (e.g., p300/CBP, AARS1/2, HBO1), erasers (HDAC1–3 and SIRT1/3), and readers (such as BRG1) that together sense metabolic signals, integrate them into epigenetic decisions, and execute transcriptional outputs. In lung cancer, lactate accumulation drives histone H3K18 lactylation (H3K18la), which activates oncogenic programs and immune‑evasion pathways—including the POM121/MYC/PD‑L1 axis in non‑small cell lung cancer and the LDH‑H3K18la‑Nur77 axis in small cell lung cancer. Non‑histone lactylation also stabilizes key proteins like RBM15 and IGF1R, further reinforcing resistance and proliferative signaling. “Our framework highlights that lactylation is not a bystander metabolite mark but an active rheostat that couples glycolysis to transcriptional plasticity,” said Yong Xu. “Targeting this axis offers a new paradigm to overcome drug resistance.”
Importantly, the review details how lactylation drives resistance across all major treatment modalities: it induces multidrug efflux and anti‑apoptotic programs in chemotherapy, impairs CD8⁺ T‑cell function and polarizes macrophages toward an M2 phenotype in immunotherapy, and sustains positive feedback loops—such as CTHRC1/glycolysis/H3K18la and NNMT‑EGR1—that underpin EGFR‑TKI resistance. The authors propose that combining lactate‑lactylation interventions with PD‑1/PD‑L1 blockade or EGFR‑TKIs may restore treatment sensitivity, and they highlight H3K18la immunohistochemistry and hyperpolarized ¹³C‑pyruvate MRI as promising pharmacodynamic biomarkers. View the full article: https://doi.org/10.1016/j.cmp.2026.03.004 .
Current Molecular Pharmacology