ALDH2 Suppresses Glycolysis in Hepatocellular Carcinoma via TRIM21-Mediated GLUT1 Degradation

Aldehyde dehydrogenase 2 (ALDH2) detoxifies alcohol-derived acetaldehyde and lipid aldehydes from lipid peroxidation. A single nucleotide polymorphism of ALDH2 rs671, representing 30-50% East Asians and featuring ALDH2 deficiency, is associated with increased risk of hepatocellular carcinoma (HCC), but the underlying mechanism remains unclear. Here we demonstrate a non-catalytic role of ALDH2 in regulating glucose metabolism through post-translational control of GLUT1 stability. Using ALDH2 knockout and rs671 knock-in mice, we show that ALDH2 interacts with GLUT1 and promotes its K48-linked ubiquitination at lysine 256 via recruitment of E3 ligase TRIM21. ALDH2 deficiency reduces GLUT1 ubiquitination, stabilizes GLUT1 protein, enhances glycolytic flux, and promotes HCC development. These effects occur independently of alcohol exposure. Pharmacological inhibition or genetic silencing of GLUT1 reverses the tumor-promoting effect of ALDH2 deficiency in both xenograft and DEN-induced models. These findings reveal an unrecognized metabolic function of ALDH2 and nominate GLUT1 as a tractable vulnerability in ALDH2-deficient HCC.