MTCH2 Deficiency Promotes E2F4/TFRC‐Mediated Ferroptosis and Sensitizes Colorectal Cancer Liver Metastasis to Sorafenib

Abstract Ferroptosis is a specific type of lipid peroxide‐mediated cell death which is crucial in tumor suppression. While the mitochondrial carrier homolog 2 (MTCH2) is implicated in lipid homeostasis and mitochondrial metabolism, its role in ferroptosis and colorectal cancer (CRC) remains uncharacterized. Here, MTCH2 is identified as a crucial regulator of ferroptosis in CRC progression. Clinically, high expression of MTCH2 in CRC tissues predicts poor prognosis. Functionally, loss of MTCH2 inhibits azoxymethane (AOM)/dextran sodium sulfate (DSS)‐induced colorectal tumorigenesis in MTCH2 cKO mice and leads to accumulation of ferrous ion and enhances ferroptosis of CRC in vitro and in vivo. Mechanistically, MTCH2 deficiency promotes the proteasome‐dependent ubiquitination of E2F4 and attenuates transcriptional inhibition of transferrin receptor (TFRC) by E2F4, ultimately facilitating TFRC‐mediated ferroptosis in CRC cells. Moreover, MTCH2 depletion combined with sorafenib treatment synergistically triggers ferroptosis, suppresses liver metastasis, and effectively eradicates tumors in liver metastasis foci. Taken together, This study reveals the mechanism of MTCH2 deficiency‐induced ferroptosis to inhibit the progression of CRC and supports a potential therapeutic strategy targeting the MTCH2/E2F4/TFRC signaling axis in CRC patients with liver metastasis.