Magnetoreceptor Promotes Hepatocellular Carcinoma Development and Blunts Sorafenib-Induced Ferroptosis by Regulating Iron Homeostasis.

Iron homeostasis plays a critical role in the pathogenesis and therapeutic management of hepatocellular carcinoma (HCC). Magnetoreceptor (MagR), also known as iron-sulfur cluster assembly protein 1 (ISCA1), is a conserved protein maintaining iron homeostasis, plays an undefined role in HCC. The present study aimed to elucidate MagR's functional involvement in HCC pathogenesis and sorafenib-induced ferroptosis, and to explore its therapeutic potential for HCC. Pan-cancer analyses showed that MagR was significantly upregulated in HCC tissues compared with normal liver tissues, accompanied with advanced stage and poor prognosis in patients. Functional experiments further demonstrated that MagR deficiency suppressed HCC cell proliferation, migration, and invasion while enhancing the sensitivity of these cells to sorafenib-induced ferroptosis, whereas overexpression of MagR had opposite effects. Mechanistically, MagR promoted HCC progression by sustaining cellular iron homeostasis and preserving mitochondrial function, and mediated ferroptosis sensitivity of HCC cells via regulating intracellular iron accumulation. Notably, in vivo studies showed that MagR ablation not only attenuated the growth of HCC xenograft tumors but also potentiated the antitumor efficacy of sorafenib. Collectively, these findings identify MagR as a potential therapeutic target for HCC and establish that therapeutic strategies targeting MagR could optimize sorafenib-based treatment regimens for this disease.