Sfxn2, a member of the SFXN protein family, is a mitochondrial outer membrane protein. It is involved in mitochondrial iron metabolism, an essential process for heme biosynthesis and iron-sulfur cluster assembly [2]. Mitochondria rely on proper iron metabolism for energy production, and thus Sfxn2 is crucial for maintaining mitochondrial homeostasis and cellular energy-related functions.

In multiple myeloma (MM), SFXN2 was found to be significantly elevated in patients, correlating with poor outcomes. SFXN2 overexpression promoted MM cell proliferation and suppressed starvation-induced autophagy/mitophagy, while knockdown aggravated mitochondrial damage and autophagic processes. In vivo, inhibition of SFXN2 showed anti-myeloma activity. The anti-oxidant function of heme oxygenase 1 (HO1) contributed to the autophagy suppression and cellular proliferation mediated by SFXN2 [1]. In SFXN2-knockout (KO) cells, mitochondrial iron content increased, accompanied by decreases in heme content and heme-dependent enzyme activities, along with impaired mitochondrial respiration and accelerated iron-mediated cell death, indicating its role in regulating heme biosynthesis [2].

In breast cancer, high SFXN2 expression was significantly associated with good prognosis [3]. In prostate cancer, SFXN2 was significantly upregulated in malignant tissues compared to benign tissues [4].

In conclusion, Sfxn2 plays a critical role in mitochondrial iron metabolism, influencing heme biosynthesis and related enzyme activities. Its dysregulation is associated with multiple cancers, such as multiple myeloma, breast cancer, and prostate cancer. Studies using KO models have provided insights into its functions in these disease-related biological processes, highlighting its potential as a therapeutic target in cancer treatment.