biostudies-literatureUnknownChen SYNIAID NIH HHSNIGMS NIH HHSNinjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis remains unknown. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that NINJ1-mediated ferroptosis protection can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diebioRxiv : the preprint server for biology2024.02.22.581432https://www.ebi.ac.uk/biostudies/studies/S-EPMC10925083biostudies-literatureNINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation.PMC10925083R01 GM124062R21 AI149205Wu JSetayeshpour YChen SYLin CCWang YEMestre AChi JTChen YfalseNINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation.Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis remains unknown. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that NINJ1-mediated ferroptosis protection can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and die2024-01-01T00:00:00Z2024 Feb2025-05-18T12:54:13.757Z2025-05-18T12:54:13.757ZS-EPMC109250833846422610.1101/2024.02.22.581432