Cancer cells preferentially accumulate iron (Fe) relative to non-malignant cells; however, the underlying rationale remains elusive. Iron-sulfur (Fe-S) clusters are critical cofactors that aid in a wide variety of cellular functions (e.g., DNA metabolism and electron transport). In this article, we theorize that a differential need for Fe-S biogenesis in tumor versus non-malignant cells underlies the Fe-dependent cell growth demand of cancer cells to promote cell division and survival by promoting genomic stability via Fe-S containing DNA metabolic enzymes. In this review, we outline the complex Fe-S biogenesis process and its potential upregulation in cancer. We also discuss three therapeutic strategies to target Fe-S biogenesis: (i) redox manipulation, (ii) Fe chelation, and (iii) Fe mimicry.
Keywords: cancer therapy; carcinogenesis; iron metabolism; iron–sulfur cluster biogenesis.