Rust and redemption: iron-sulfur clusters and oxygen in human disease and health

Iron-sulfur (Fe-S) clusters are ancient and versatile cofactors that drive essential cellular functions, from electron transport to enzyme catalysis. Their intrinsic sensitivity to oxidation has shaped the evolution of specialized Fe-S cluster biosynthetic and protective mechanisms. Recent findings highlight how human Fe-S-binding regulators exploit this cofactor's reactivity to sense iron and oxygen levels, translating environmental cues into appropriate homeostatic responses. Yet, the same redox sensitivity also renders Fe-S cluster proteins and biosynthesis particularly vulnerable to high oxygen tensions, contributing to pathological outcomes. In this minireview, we examine key discoveries illustrating how Fe-S clusters and oxygen intersect to influence both human health and disease. Finally, we discuss how identifying novel Fe-S targets and regulatory circuits may open innovative therapeutic avenues-harnessing oxygen itself as a strategic element in managing relevant disorders.