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. 2025 May 15;188(10):2569-2585.e20.
doi: 10.1016/j.cell.2025.03.019. Epub 2025 Apr 14.

ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1

Jia-Shu Yang  1 , Andrew J Morris  2 , Koki Kamizaki  3 , Jianzhong Chen  4 , Jillian Stark  5 , William M Oldham  6 , Toshitaka Nakamura  7 , Eikan Mishima  7 , Joseph Loscalzo  8 , Yasuhiro Minami  3 , Marcus Conrad  7 , Whitney S Henry  5 , Victor W Hsu  9
Affiliations

ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1

Jia-Shu Yang et al. Cell. .

Abstract

Ferroptosis is a form of cell death due to iron-induced lipid peroxidation. Ferroptosis suppressor protein 1 (FSP1) protects against this death by generating antioxidants, which requires nicotinamide adenine dinucleotide, reduced form (NADH) as a cofactor. We initially uncover that NADH exists at significant levels on cellular membranes and then find that this form of NADH is generated by aldehyde dehydrogenase 7A1 (ALDH7A1) to support FSP1 activity. ALDH7A1 activity also acts directly to decrease lipid peroxidation by consuming reactive aldehydes. Furthermore, ALDH7A1 promotes the membrane recruitment of FSP1, which is instigated by ferroptotic stress activating AMP-activated protein kinase (AMPK) to promote the membrane localization of ALDH7A1 that stabilizes FSP1 on membranes. These findings advance a fundamental understanding of NADH by revealing a previously unappreciated pool on cellular membranes, with the elucidation of its function providing a major understanding of how FSP1 acts and how an aldehyde dehydrogenase protects against ferroptosis.

Keywords: aldehyde dehydrogenase 7A1; ferroptosis; ferroptosis suppressor protein 1; nicotinamide adenine dinucleotide reduced form.

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Conflict of interest statement

Declaration of interests M.C. is a co-founder and shareholder of ROSCUE Therapeutics GmbH.

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