Discovery of an NADPH sensor for the regulation of ferroptotic cell death

Ferroptosis is a novel type of regulated cell death driven by excessive iron-dependent lipid peroxidation. The levels of the biosynthetic reductant NADPH is suggested to be a predictable biomarker for the assessment of ferroptosis sensitivity. However, specific regulator(s) that sense cellular NADPH levels, thereby controlling downstream ferroptosis events, remained unknown.

Koran researchers at Pohang University of Science and Technology (POSTECH) discovered that the transmembrane endoplasmic reticulum (ER) MARCHF6 E3 ubiquitin ligase recognizes NADPH through its C-terminal regulatory region. This recognition augments the E3 ligase activity of MARCHF6, thus suppressing ferroptosis. They also found that MARCHF6 promotes the degradation of the central pro-ferroptosis effectors ACSL4 and p53. Furthermore, inhibiting ferroptosis rescued the growth of MARCHF6-deficient tumours and perinatal lethality of Marchf6–/– knock-out mice. Altogether, these findings identify MARCHF6 as a novel NADPH sensor in the ubiquitin system and a core regulator of ferroptosis. This study is published in Nature Cell Biology in Aug 8, 2022.

Profs. Cheol-Sang Hwang and Yoontae Lee said that "We discovered the MARCHF6 E3 ligase as the first NADPH sensor in ubiquitin system and a core regulator for ferroptosis. Since perturbations of MARCHF6 are directly or indirectly linked to many human diseases, including cancers, nervous system disorders and complex metabolic syndroms, our current findings suggest that dysregulation of MARCHF6 might underlie those diseases due to elevated ferroptotic cell death. Moreover, given that a major role of MARCHF6 is defined as a central regulator of ferroptosis, it can now be a promising drug target.“

[Reference] Nguyen TK, et al., (2022) “The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis.” Nature Cell Biology 24, 1239–1251 (2022).

[Main Author] 1st author, Dr. Nguyen the Kha (POSTECH). Corresponding authors: Prof. Cheol-Sang Hwang (cshwang@postech.ac.kr) and prof. Yoontae Lee (yoontael@postech.ac.kr)