Elevated SFXN2 limits mitochondrial autophagy and increases iron-mediated energy production to promote multiple myeloma cell proliferation.

Human sideroflexin 2 (SFXN2) belongs to the SFXN protein family, which is a mitochondrial outer membrane protein involved in mitochondrial iron metabolism. Mitochondria are indispensable for cellular energy production and iron metabolism. However, it remains elusive how SFXN2 modulates mitochondrial homeostasis and cellular iron metabolism in multiple myeloma (MM). In this study, we first found that SFXN2 was significantly elevated and correlated to poor outcomes in MM patients from clinical datasets. SFXN2 overexpression promoted MM cell proliferation and suppressed starvation-induced autophagy/mitophagy, while SFXN2 knockdown aggravated mitochondria damage and autophagic processes in ARP1 and H929 MM cell lines. Furthermore, inhibition of SFXN2 exerted effectively anti-myeloma activity in vivo by using myeloma xenograft model. Mechanism studies indicated that heme oxygenase 1 (HO1) with anti-oxidant function contributed to the process of autophagy suppression and cellular proliferation mediated by SFXN2. Our study revealed the critical role of SFXN2 in regulating mitochondrial bioenergetics, mitophagy, cellular iron metabolism, and redox homeostasis in interconnected and intricate way. Collectively, these findings not only provide insights into the metabolic reprogramming of tumor cells, but also highlight the therapeutic potential of SFXN2 in combination with iron metabolism as target for prognosis and treatment in MM patients.