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.

人 sideroflexin 2 (SFXN2) 属于 SFXN 蛋白家族，是一种参与线粒体铁代谢的线粒体外膜蛋白。线粒体对于细胞能量产生和铁代谢是必不可少的。然而，SFXN2 如何调节多发性骨髓瘤 (MM) 中的线粒体稳态和细胞铁代谢仍然难以捉摸。在这项研究中，我们首先发现 SFXN2 显着升高并与临床数据集中 MM 患者的不良结果相关。SFXN2 过表达促进 MM 细胞增殖并抑制饥饿诱导的自噬/线粒体自噬，而 SFXN2 敲低加剧了 ARP1 和 H929 MM 细胞系中的线粒体损伤和自噬过程。此外，通过使用骨髓瘤异种移植模型，抑制 SFXN2 在体内有效发挥抗骨髓瘤活性。机制研究表明，具有抗氧化功能的血红素加氧酶 1 (HO1) 有助于 SFXN2 介导的自噬抑制和细胞增殖过程。我们的研究揭示了 SFXN2 在以相互关联和复杂的方式调节线粒体生物能量学、线粒体自噬、细胞铁代谢和氧化还原稳态中的关键作用。总的来说，这些发现不仅提供了对肿瘤细胞代谢重编程的见解，而且突出了 SFXN2 结合铁代谢作为 MM 患者预后和治疗靶点的治疗潜力。我们的研究揭示了 SFXN2 在以相互关联和复杂的方式调节线粒体生物能量学、线粒体自噬、细胞铁代谢和氧化还原稳态中的关键作用。总的来说，这些发现不仅提供了对肿瘤细胞代谢重编程的见解，而且突出了 SFXN2 结合铁代谢作为 MM 患者预后和治疗靶点的治疗潜力。我们的研究揭示了 SFXN2 在以相互关联和复杂的方式调节线粒体生物能量学、线粒体自噬、细胞铁代谢和氧化还原稳态中的关键作用。总的来说，这些发现不仅提供了对肿瘤细胞代谢重编程的见解，而且突出了 SFXN2 结合铁代谢作为 MM 患者预后和治疗靶点的治疗潜力。