biostudies-literatureBelavgeni ADeutsche Forschungsgemeinschafte2300320120https://www.ebi.ac.uk/biostudies/studies/S-EPMC10214148biostudies-literatureUnknown120(21)Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin receptors (IRs) and insulin-like growth factor receptors. The homology of VILPs includes highly conserved disulfide bridges. However, the binding affinities to IRs were reported to be 200- to 500-fold less effective compared to the endogenous ligands. We therefore speculated that these peptides also have noninsulin functions. Here, we report that the LCDV-1 VILP can function as a potent and highly specific inhibitor of ferroptosis. Induction of cell death by the ferroptosis inducers erastin, RSL3, FIN56, and FINO2 and nonferroptotic necrosis produced by the thioredoxin-reductase inhibitor ferroptocide were potently prevented bProceedings of the National Academy of Sciences of the United States of AmericavPIF-1 is an insulin-like antiferroptotic viral peptide.PMC10214148460938556503200509314061271Tonnus WGavali SBornstein SRSha WFlade KMaremonti FBeer KGembardt FHugo CGiacca MLinkermann AStadtmuller MBecker JNHale BGStumpf JSchally AVMallais MTmava MPerakakis NPratt DABelavgeni ABrucker AfalsevPIF-1 is an insulin-like antiferroptotic viral peptide.Iridoviridae, such as the lymphocystis disease virus-1 (LCDV-1) and other viruses, encode viral insulin-like peptides (VILPs) which are capable of triggering insulin receptors (IRs) and insulin-like growth factor receptors. The homology of VILPs includes highly conserved disulfide bridges. However, the binding affinities to IRs were reported to be 200- to 500-fold less effective compared to the endogenous ligands. We therefore speculated that these peptides also have noninsulin functions. Here, we report that the LCDV-1 VILP can function as a potent and highly specific inhibitor of ferroptosis. Induction of cell death by the ferroptosis inducers erastin, RSL3, FIN56, and FINO2 and nonferroptotic necrosis produced by the thioredoxin-reductase inhibitor ferroptocide were potently prevented b2023-01-01T00:00:00Z2023 May2025-04-05T08:50:48.975Z2025-04-05T08:50:48.975ZS-EPMC102141483718684510.1073/pnas.2300320120