biostudies-literatureUnknown119(36)Ta NFerroptosis is an iron-dependent programmed necrosis characterized by glutathione (GSH) depletion and lipid peroxidation (LPO). Armed with both the pro- and antiferroptosis machineries, mitochondria play a central role in ferroptosis. However, how mitochondria sense the stress to activate ferroptosis under (patho-)physiological settings remains incompletely understood. Here, we show that FUN14 domain-containing 2, also known as HCBP6 (FUNDC2), a highly conserved and ubiquitously expressed mitochondrial outer membrane protein, regulates ferroptosis and contributes to doxorubicin (DOX)-induced cardiomyopathy. We showed that knockout of FUNDC2 protected mice from DOX-induced cardiac injury by preventing ferroptosis. Mechanistic studies reveal that FUNDC2 interacts with SLC25A11, the mitochondProceedings of the National Academy of Sciences of the United States of Americae2117396119https://www.ebi.ac.uk/biostudies/studies/S-EPMC9457330biostudies-literatureMitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy.PMC9457330Qu CLi YChen QZhang DLiu LSun TWang XTang TTa NWang JWu HfalseMitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy.Ferroptosis is an iron-dependent programmed necrosis characterized by glutathione (GSH) depletion and lipid peroxidation (LPO). Armed with both the pro- and antiferroptosis machineries, mitochondria play a central role in ferroptosis. However, how mitochondria sense the stress to activate ferroptosis under (patho-)physiological settings remains incompletely understood. Here, we show that FUN14 domain-containing 2, also known as HCBP6 (FUNDC2), a highly conserved and ubiquitously expressed mitochondrial outer membrane protein, regulates ferroptosis and contributes to doxorubicin (DOX)-induced cardiomyopathy. We showed that knockout of FUNDC2 protected mice from DOX-induced cardiac injury by preventing ferroptosis. Mechanistic studies reveal that FUNDC2 interacts with SLC25A11, the mitochond2022-01-01T00:00:00Z2022 Sep2025-04-04T08:53:42.528Z2025-04-04T08:53:42.528ZS-EPMC94573303603733710.1073/pnas.2117396119