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. 2025 Jun 3;37(6):1326-1343.e10.
doi: 10.1016/j.cmet.2025.03.014. Epub 2025 Apr 14.

Cytosolic cytochrome c represses ferroptosis

Xinxin Song  1 , Zhuan Zhou  1 , Jiao Liu  2 , Jingbo Li  1 , Chunhua Yu  1 , Herbert J Zeh  1 , Daniel J Klionsky  3 , Brent R Stockwell  4 , Jiayi Wang  5 , Rui Kang  6 , Guido Kroemer  7 , Daolin Tang  8
Affiliations

Cytosolic cytochrome c represses ferroptosis

Xinxin Song et al. Cell Metab. .

Abstract

The release of cytochrome c, somatic (CYCS) from mitochondria to the cytosol is an established trigger of caspase-dependent apoptosis. Here, we unveil an unexpected role for cytosolic CYCS in inhibiting ferroptosis-a form of oxidative cell death driven by uncontrolled lipid peroxidation. Mass spectrometry and site-directed mutagenesis revealed the existence of a cytosolic complex composed of inositol polyphosphate-4-phosphatase type I A (INPP4A) and CYCS. This CYCS-INPP4A complex is distinct from the CYCS-apoptotic peptidase activating factor 1 (APAF1)-caspase-9 apoptosome formed during mitochondrial apoptosis. CYCS boosts INPP4A activity, leading to increased formation of phosphatidylinositol-3-phosphate, which prevents phospholipid peroxidation and plasma membrane rupture, thus averting ferroptotic cell death. Unbiased screening led to the identification of the small-molecule compound 10A3, which disrupts the CYCS-INPP4A interaction. 10A3 sensitized cultured cells and tumors implanted in immunocompetent mice to ferroptosis. Collectively, these findings redefine our understanding of cytosolic CYCS complexes that govern diverse cell death pathways.

Keywords: apoptosis; cytochrome c; ferroptosis; protein complex.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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