Regulatory networks of iron sulfur cluster biology in cancer mechanisms and therapeutic perspectives

Iron-sulfur (Fe/S) clusters are essential cofactors required for mitochondrial metabolism, redox regulation, DNA synthesis, and cellular viability. Defects in their biogenesis or function compromise mitochondrial homeostasis, iron balance, and genome stability, alterations frequently observed in cancer. Growing evidence indicates that Fe/S proteins participate in tumor cell proliferation, metabolic adaptation, oxidative stress tolerance, and therapeutic resistance. This review summarizes current knowledge on the mechanisms of Fe/S cluster assembly in distinct cellular compartments, including the mitochondria, cytosol, and nucleus, and outlines their physiological roles in normal and malignant cells. It further discusses the molecular mechanisms by which dysregulation of Fe/S cluster homeostasis contributes to tumorigenesis. In addition, we highlight emerging therapeutic strategies that exploit Fe/S cluster dependencies, including small-molecule approaches, regulated cell death pathways, and nanomedicine-based interventions. Collectively, these insights underscore the relevance of Fe/S cluster biology to cancer pathogenesis and its potential for therapeutic exploitation.