Regulation of Ferroptosis by a novel NADPH phosphatase MESH1

Ferroptosis is a form of regulated cell death featured by lipid peroxidation and breakage of cell membrane. However, the molecular mediators and regulators are not fully understood. Here, we identified the metazoan homologues of ppGpp hydrolase (MESH1) is an efficient cytosolic NADPH phosphatase, an unexpected enzymatic activity that is captured by the crystal structure of the MESH1-NADPH complex. Ferroptosis elevates MESH1, whose upregulation depletes NADPH and sensitizes cells to ferroptosis. Conversely, MESH1 depletion rescues ferroptosis by sustaining the levels of NADPH and GSH and by reducing lipid peroxidation. Importantly, the ferroptotic protection by MESH1 depletion is ablated by suppression of the cytosolic NAD(H) kinase, NADK, but not its mitochondrial counterpart NADK2. MESH1 depletion also triggers extensive transcriptional changes that are distinct from the canonical integrated stress response, but show striking similarity to the bacterial stringent response. MESH1 depletion also leads to dNTP depletion and inhibition of cell proliferation in tumor cells. Finally, we established Mesh1 knockout mouse model to study the physiological relevance of MESH1.