{
  "abstract": "Background Iron is an essential cofactor for mitochondrial metabolism, yet the regulatory mechanisms linking cellular iron homeostasis to colorectal cancer (CRC) progression remain poorly defined. This study aimed to determine how nuclear receptor coactivator 4 (NCOA4)—a selective ferritinophagy receptor—regulates cytosolic and mitochondrial iron handling and influences CRC tumorigenesis.Methods Human colorectal cancer (CRC) specimens and colonspecific Ncoa4 knockout mice were used to assess the biological effects of NCOA4 loss. CRC cell lines with genetic or pharmacological manipulation of NCOA4, mitochondrial calcium uniporter (MCU), and signal transducer and activator of transcription 3 (STAT3) were employed to define underlying mechanisms. Ferritinophagy activity and iron metabolism were evaluated through biochemical assays, iron quantification, and mitochondrial functional analyses. Protein expression profiling examined how NCOA4 loss affects transferrin receptor–mediated iron uptake and MCUdependent mitochondrial iron import. Tumorigenesis was assessed in Ncoa4deficient mouse models, and inhibitors targeting MCU, STAT3, or mitochondrial iron transport were tested for their ability to reduce tumor growth. NCOA4 overexpression models were used to determine whether restoring ferritinophagy suppresses tumor progression.Results Loss of NCOA4 in human tumors and mouse models induced a dual pattern of iron overload: (1) increased transferrin receptor–driven cytosolic iron uptake, and (2) enhanced MCU-dependent mitochondrial iron import. The resulting mitochondrial iron excess elevated mitochondrial reactive oxygen species (mROS), activated STAT3 signaling, and promoted CRC cell proliferation and tumorigenesis. Pharmacological blockade of MCU, STAT3, or mitochondrial iron transport mitigated tumor growth in NCOA4-deficient mice. Restoration of NCOA4 expression reversed tumor progression and reduced MCU levels, normalizing mitochondrial iron metabolism.Conclusions These findings identify NCOA4 as a tumor suppressor that coordinates cytosolic and mitochondrial iron regulation in CRC. The NCOA4–MCU–STAT3 signaling axis links ferritinophagy dysregulation to oncogenic progression and highlights mitochondrial iron handling as a promising therapeutic vulnerability in colorectal cancer.",
  "authors": [
    {
      "affiliations": [
        "University of New Mexico, United States"
      ],
      "name": "Xiang Xue"
    },
    {
      "affiliations": [
        "University of New Mexico, United States"
      ],
      "name": "Hyeoncheol Kim"
    },
    {
      "affiliations": [
        "University of New Mexico, United States"
      ],
      "name": "Luke Villareal"
    },
    {
      "affiliations": [
        "Harvard Medical School, United States"
      ],
      "name": "Naiara Santana-Codina"
    },
    {
      "affiliations": [
        "University of New Mexico, United States"
      ],
      "name": "Christian Cabanlong"
    },
    {
      "affiliations": [
        "University of New Mexico, United States"
      ],
      "name": "Lavanya Goodla"
    },
    {
      "affiliations": [
        "University of New Mexico, United States"
      ],
      "name": "Xiangxiang Wu"
    },
    {
      "affiliations": [
        "University of New Mexico, United States"
      ],
      "name": "Eric Prossnitz"
    },
    {
      "affiliations": [
        "University of New Mexico, United States"
      ],
      "name": "David Martin"
    },
    {
      "affiliations": [
        "Harvard Medical School, United States"
      ],
      "name": "Joseph Mancias"
    }
  ],
  "title": "IDDF2026-ABS-0023 NCOA4 suppresses colorectal tumorigenesis through restricting MCU-dependent mitochondrial iron overload and STAT3 activation",
  "uid": "2f1907b0-9b2a-5960-91b8-d4737c878708"
}