(−)‐Epicatechin Regulates Radioresistance in Lung Adenocarcinoma Through ALKBH5 Downregulation of FOXM1

Lung adenocarcinoma (LUAD), a major subtype of non-small-cell lung cancer, exhibits high incidence and mortality rates. Radiotherapy is a critical treatment modality for LUAD, yet its efficacy is often compromised by radiotherapy resistance. (-)-Epicatechin (EC), a natural flavanol derived from Fagopyrum cymosum, has been reported to enhance radiosensitivity in various cancers. However, its specific role and underlying mechanisms in LUAD radiotherapy resistance remain unclear. In this study, we established radiotherapy-resistant cell lines A549R and NCI-H520R by repeatedly irradiating A549 and NCI-H520 cells with gradient doses of X-rays. Furthermore, a xenograft tumor model was constructed by subcutaneously inoculating A549R cells into the left dorsal region of nude mice. The results demonstrated that the forkhead box M1 (FOXM1)-a key oncoprotein implicated in lung cancer proliferation, invasion, and therapy resistance-was significantly upregulated in LUAD tissues and radiotherapy-resistant A549R cells. Knockdown of FOXM1 enhanced radiosensitivity in A549R cells, promoted radiation-induced apoptosis, and suppressed cell proliferation. EC effectively potentiated the radiotherapy response of A549R cells in vitro and attenuated radiotherapy resistance while inhibiting tumor growth in vivo. Mechanistically, EC downregulated ALKBH5, an m6A demethylase known to participate in cancer biology by regulating mRNA demethylation, thereby promoting m6A methylation of FOXM1 mRNA and subsequently suppressing FOXM1 expression, ultimately mitigating radiotherapy resistance in LUAD. This study reveals a novel mechanism by which EC enhances radiosensitivity in LUAD via the ALKBH5/FOXM1 axis, offering a potential therapeutic strategy to overcome radiotherapy resistance in LUAD.