Ferroptosis, a non-apoptotic form of cell death marked by iron-dependent lipid peroxidation¹, has a key role in organ injury, degenerative disease and vulnerability of therapy-resistant cancers². Although substantial progress has been made in understanding the molecular processes relevant to ferroptosis, additional cell-extrinsic and cell-intrinsic processes that determine cell sensitivity toward ferroptosis remain unknown. Here we show that the fully reduced forms of vitamin K—a group of naphthoquinones that includes menaquinone and phylloquinone³—confer a strong anti-ferroptotic function, in addition to the conventional function linked to blood clotting by acting as a cofactor for γ-glutamyl carboxylase. Ferroptosis suppressor protein 1 (FSP1), a NAD(P)H-ubiquinone reductase and the second mainstay of ferroptosis control after glutathione peroxidase-4^4,5, was found to efficiently reduce vitamin K to its hydroquinone, a potent radical-trapping antioxidant and inhibitor of (phospho)lipid peroxidation. The FSP1-mediated reduction of vitamin K was also responsible for the antidotal effect of vitamin K against warfarin poisoning. It follows that FSP1 is the enzyme mediating warfarin-resistant vitamin K reduction in the canonical vitamin K cycle⁶. The FSP1-dependent non-canonical vitamin K cycle can act to protect cells against detrimental lipid peroxidation and ferroptosis.

Sarcopenia is associated with increased morbidity and mortality in chronic kidney disease (CKD). Pathogenic mechanism of skeletal muscle loss in CKD, which is defined as uremic sarcopenia, remains unclear. We found that causative pathological mechanism of uremic sarcopenia is metabolic alterations by uremic toxin indoxyl sulfate. Imaging mass spectrometry revealed indoxyl sulfate accumulated in muscle tissue of a mouse model of CKD. Comprehensive metabolomics revealed that indoxyl sulfate induces metabolic alterations such as upregulation of glycolysis, including pentose phosphate pathway acceleration as antioxidative stress response, via nuclear factor (erythroid-2-related factor)-2. The altered metabolic flow to excess antioxidative response resulted in downregulation of TCA cycle and its effected mitochondrial dysfunction and ATP shortage in muscle cells. In clinical research, a significant inverse association between plasma indoxyl sulfate and skeletal muscle mass in CKD patients was observed. Our results indicate that indoxyl sulfate is a pathogenic factor for sarcopenia in CKD.

Significance Statement: Ferroptosis, cell death mediated by free radical reactions and driven by oxidative degradation of lipids, is a therapeutic target because of its role in organ injuries, including AKI. However, the ferroptosis-causing radicals targeted by ferroptosis suppressors have not been unequivocally identified. Certain cytochrome P450 substrate drugs are known to prevent lipid peroxidation via obscure mechanisms. The authors screened cytochrome P450 substrate drugs, identifying a diverse group of drugs with antiferroptotic properties, including promethazine and rifampicin. The antiferroptotic effect of these drugs was linked to their scavenging activity against lipid peroxyl radicals. Elevated lipid peroxyl radical levels were associated with ferroptosis onset, whereas radical scavenging by the drugs suppressed ferroptosis-related pathologic changes in different renal cell types and ameliorated organ injuries (including AKI) in mice, suggesting therapeutic potential for such repurposed drugs. Background: Ferroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation via obscure mechanisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals. Methods: Using a cell-based assay, we screened cytochrome P450 substrate compounds to identify drugs with antiferroptotic activity and investigated the underlying mechanism. To evaluate radical-scavenging activity, we used electron paramagnetic resonance–spin trapping methods and a fluorescence probe for lipid radicals, NBD-Pen, that we had developed. We then assessed the therapeutic potency of these drugs in mouse models of cisplatin-induced AKI and LPS/galactosamine-induced liver injury. Results: We identified various US Food and Drug Administration–approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, propranolol, estradiol, and thyroid hormones. The antiferroptotic drug effects were closely associated with the scavenging of lipid peroxyl radicals but not significantly related to interactions with other radicals. The elevated lipid peroxyl radical levels were associated with ferroptosis onset, and known ferroptosis suppressors, such as ferrostatin-1, also functioned as lipid peroxyl radical scavengers. The drugs exerted antiferroptotic activities in various cell types, including tubules, podocytes, and renal fibroblasts. Moreover, in mice, the drugs ameliorated AKI and liver injury, with suppression of tissue lipid peroxidation and decreased cell death. Conclusions: Although elevated lipid peroxyl radical levels can trigger ferroptosis onset, some drugs that scavenge lipid peroxyl radicals can help control ferroptosis-related disorders, including AKI.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease, including end-stage kidney disease, and increases the risk of cardiovascular mortality. Although the treatment options for DKD, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists, have advanced, their efficacy is still limited. Thus, a deeper understanding of the molecular mechanisms of DKD onset and progression is necessary for the development of new and innovative treatments for DKD. The complex pathogenesis of DKD includes various different pathways, and the mechanisms of DKD can be broadly classified into inflammatory, fibrotic, metabolic, and hemodynamic factors. Here, we summarize the recent findings in basic research, focusing on each factor and recent advances in the treatment of DKD. Collective evidence from basic and clinical research studies is helpful for understanding the definitive mechanisms of DKD and their regulatory systems. Further comprehensive exploration is warranted to advance our knowledge of the pathogenesis of DKD and establish novel treatments and preventive strategies.