Targeting ALDH2 to augment platinum-based chemosensitivity through ferroptosis in lung adenocarcinoma

Ferroptosis is a regulated cell death driven by iron-dependent lipid peroxidation and associated with drug resistance in lung adenocarcinoma (LUAD). It's found that aldehyde dehydrogenase 2 (ALDH2), which is highly mutated in East Asian populations, is correlated with response to chemotherapy in LUAD patients. The rs671 variant knock-in, downregulation, and pharmacological inhibition of ALDH2 render LUAD cells more vulnerable to ferroptosis inducers and platinum-based chemotherapy. ALDH2 inhibits ferroptosis through the detoxification of 4-hydroxynonenal and malondialdehyde, the product of lipid peroxidation, as well as the production of NADH at the same time. Besides, ALDH2 deficiency leads to elevated intracellular pH (pHi), thus inhibiting the ERK/CREB1/GPX4 axis. Interestingly, ALDH2 is also regulated by CREB1, and the ALDH2 enzyme activity was decreased with elevated pHi. What's more, the elevated pHi caused by impaired ALDH2 activity promotes the biosynthesis of lipid droplets to counteract ferroptosis. At last, the effect of ALDH2 on ferroptosis and chemosensitivity is confirmed in patient-derived organoids and xenograft models. Collectively, this study demonstrates that ALDH2 deficiency confers sensitivity to platinum through ferroptosis in LUAD, and targeting ALDH2 is a promising new strategy to enhance the sensitivity of platinum-based chemotherapy for the treatment of LUAD patients.