biostudies-literatureWittig JHector Fellow AcademyDeutsche ForschungsgemeinschaftNational Natural Science Foundation of China103926https://www.ebi.ac.uk/biostudies/studies/S-EPMC12721145biostudies-literatureUnknown89Endogenously generated sulfides are conserved among species and tissues and exert multiple effects through diverse mechanisms. Although sulfides have been linked to cell fates, their role in pluripotent stem cell commitment remains unknown. Here we discovered that during directed differentiation of induced pluripotent stem cells, endogenous sulfide levels drop in all three germ layers, with the mesodermal lineage exhibiting the lowest capacity to generate these species at early specification events. Addition of a rapid releasing sulfide donor in iPSCs or mesodermal cells did not affect the redox surveillance mechanisms, however, it altered persulfidation and transcription of cell fate commitment pathways. In particular, sulfide supplementation in pluripotent stem cells reduced cell differeRedox biologyPersulfidation alters gene regulatory programs and promotes endothelial specification.PMC1272114539404578ProgrammeBI 2163/1\u20132BCRC1531820705014566879193235002182271479Wittig JWittig IXu RBibli SIDu YTheodorou IBo CDrekolia MKHu JHanyu CYuanyuan LGunther SChen YGupta LDelgado Lagos FZhang BOla RfalsePersulfidation alters gene regulatory programs and promotes endothelial specification.Endogenously generated sulfides are conserved among species and tissues and exert multiple effects through diverse mechanisms. Although sulfides have been linked to cell fates, their role in pluripotent stem cell commitment remains unknown. Here we discovered that during directed differentiation of induced pluripotent stem cells, endogenous sulfide levels drop in all three germ layers, with the mesodermal lineage exhibiting the lowest capacity to generate these species at early specification events. Addition of a rapid releasing sulfide donor in iPSCs or mesodermal cells did not affect the redox surveillance mechanisms, however, it altered persulfidation and transcription of cell fate commitment pathways. In particular, sulfide supplementation in pluripotent stem cells reduced cell differe2025-01-01T00:00:00Z2025 Nov2026-06-08T03:10:29.328Z2026-06-08T03:08:22.786ZS-EPMC127211454134415710.1016/j.redox.2025.103926