Abstract
Iron is an essential cofactor for mitochondrial metabolism, yet the regulatory networks linking cellular iron homeostasis to colorectal cancer (CRC) progression remain incompletely understood. Here, we identify nuclear receptor coactivator 4 (NCOA4), a ferritinophagy receptor, as a context-dependent tumor suppressor that coordinates cytosolic and mitochondrial iron handling in CRC. Analysis of human tumors and colon-specific Ncoa4 knockout mice revealed that NCOA4 loss drives tumorigenesis by inducing transferrin receptor-mediated iron uptake and mitochondrial calcium uniporter (MCU)-dependent mitochondrial iron import. This dual iron overload elevates mitochondrial reactive oxygen species, activates STAT3 signaling, and enhances tumor cell proliferation. NCOA4 overexpression reverses these effects, reducing MCU expression and tumor growth. Pharmacological inhibition of MCU, STAT3, or mitochondrial iron transport mitigated tumorigenesis in NCOA4-deficient models. Our findings define an NCOA4-MCU-STAT3 metabolic signaling axis that couples iron metabolism to oncogenic progression and reveal mitochondrial iron handling as a therapeutic vulnerability in CRC.