ALDH2 inhibits head and neck tumorigenesis through RAS signaling suppression, transactivation of TGM2, and synergy with ALDH6A1.

Head and neck squamous cell carcinoma (HNSC) ranks among the most common malignancies globally, with ALDH2 mutations linked to elevated disease risk. This study delineates the tumor-suppressive functions of ALDH2, examining its enzymatic activity, post-translational modifications, potentially transcriptional regulation, and protein–protein interactions. In an oral squamous cell carcinoma (OSCC) cohort, high ALDH2 immunostaining independently correlated with improved clinical outcomes. Functional assays across four HNSC-derived cell lines revealed that ALDH2 inhibits anchorage-independent growth, migration, invasion, and endothelial tube formation effects mediated by suppression of the HRAS–AKT–NFκB signaling axis. Mutations at E504 and phosphorylation-deficient variants at T261 and S488 impaired ALDH2 enzymatic function and abolished its tumor-suppressive capacity by reactivating oncogenic signaling. Mechanistically, ALDH2-mediated inhibition of AKT1 reduced NR4A1 phosphorylation, thereby enhancing TGM2 transcription and translation and promoting apoptosis. Notably, ALDH2 directly interacts with ALDH6A1, and this association, independent of catalytic activity, synergistically amplifies anti-tumor signaling. Collectively, these findings identify ALDH2 as a key tumor suppressor in HNSC, including OSCC, and highlight the therapeutic potential of activating ALDH2, NR4A1, and TGM2. Moreover, stabilization of the ALDH2–ALDH6A1 complex may offer a viable strategy for disease prevention and treatment, even in the context of frequent ALDH2 mutations. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-025-06027-7.