Metabolic-Epigenetic Regulation of TRPM3 via H3K18 Lactylation in Dorsal Root Ganglia Mediates Bone Cancer Pain and Its Attenuation by Microwave Ablation
Cancer Lett. 2026 Apr 13:218505. doi: 10.1016/j.canlet.2026.218505. Online ahead of print.
ABSTRACT
Bone metastatic pain in lung cancer remains difficult to control and its molecular drivers are incompletely defined. Here, integrating a clinical cohort with mechanistic models, we delineate a tumor metabolism-neural epigenetic-ion-channel axis. In patients with lung cancer bone metastases, 63% reported moderate-severe pain, and higher preoperative VAS scores associated with shorter overall survival. Single-cell RNA-sequencing of metastatic lesions demonstrated glycolysis enrichment in tumor cells from patients with higher pain, and dorsal root ganglia (DRG) from these patients exhibited stronger pan-lysine lactylation, which positively correlated with VAS. In mice, a femoral Lewis lung carcinoma model recapitulated progressive mechanical allodynia, thermal hyperalgesia, locomotor impairment, systemic hyperlactatemia, and increased DRG lactylation. Intrathecal lactate in naïve mice induced DRG lactylation and hypersensitivity, whereas intrathecal oxamate in tumor-bearing mice attenuated both, establishing a causal role for lactate signaling. CUT&Tag profiling revealed a marked gain of H3K18 lactylation at the Trpm3 promoter in tumor DRG, with concordant upregulation of Trpm3 mRNA and TRPM3 protein; Trpm3-/- mice displayed blunted thermal and mechanical pain behaviors. Therapeutically, CT-guided microwave ablation (MWA) of femoral tumors produced significant analgesia and functional improvement, reduced DRG H3K18 lactylation and TRPM3, and, in vitro, suppressed tumor glycolytic proteins (HK2, MCT1, GLUT1). These findings identify a targetable lactate-H3K18 lactylation-TRPM3 pathway in bone metastatic pain and support MWA as a mechanism-based palliative strategy that modulates the metabolic-epigenetic drivers of nociceptor sensitization.
PMID:41985872 | DOI:10.1016/j.canlet.2026.218505