{
  "abstract": "Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality, and the clinical utility of β-lapachone (β-Lap) is limited by dose-dependent toxicity. Here, we identify cryptotanshinone (CPT), a bioactive compound derived from Salvia miltiorrhiza , as a synergistic partner that enables dose reduction while enhancing antitumor efficacy. Integrated transcriptomic profiling, biochemical analyses, target engagement assays, and in vivo validation support that β-Lap and CPT cooperatively induce ferroptosis through disruption of iron–redox homeostasis. Mechanistically, β-Lap and CPT engage Raptor and mTOR, respectively, in vitro, supporting a model wherein their cooperative action leads to dual suppression of mTORC1 signaling. mTORC1 inhibition activates NCOA4-mediated ferritinophagy, promoting ferritin degradation and expansion of the labile Fe 2+ pool. The consequent iron-dependent Fenton reaction drives excessive reactive oxygen species (ROS) accumulation and lipid peroxidation, culminating in ferroptotic cell death. Notably, this process occurs without downregulation of the canonical GPX4-SLC7A11 axis, defining a non-canonical, iron-amplified ferroptosis pathway. In xenograft models, the combination therapy significantly suppressed tumor growth without detectable systemic toxicity and recapitulated the molecular hallmarks observed in vitro, including mTORC1 inhibition, enhanced ferritinophagy, iron overload, and lipid peroxidation. Collectively, our findings support cooperative mTORC1 inhibition as a strategy to trigger ferritinophagy-dependent iron–redox collapse and non-canonical ferroptosis, providing a mechanistically informed and low-toxicity therapeutic approach for HCC.",
  "abstract_shown": true,
  "affiliations": [
    "Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China",
    "Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Department of Laboratory Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China",
    "Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China",
    "Department of Pathology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China; Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, China",
    "Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China",
    "Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China; Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China",
    "State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, 999078, Macao Special Administrative Region of China",
    "Sichuan Key Medical Laboratory of New Drug Discovery and Drug Ability Evaluation, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China; Corresponding author.",
    "Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Department of Laboratory Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China; Corresponding author."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "name": "Xinyu Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhen Tan"
    },
    {
      "affs": [
        1
      ],
      "name": "Shiqiao Zhao"
    },
    {
      "affs": [
        2
      ],
      "name": "Fan Li"
    },
    {
      "affs": [
        3
      ],
      "name": "Yilin Liu"
    },
    {
      "affs": [
        4
      ],
      "name": "Cong Ren"
    },
    {
      "affs": [
        5
      ],
      "name": "Jiaying Li"
    },
    {
      "affs": [
        6
      ],
      "name": "Hanghong Lo"
    },
    {
      "affs": [
        1
      ],
      "name": "Yue Cui"
    },
    {
      "affs": [
        1
      ],
      "name": "Aie Zhou"
    },
    {
      "affs": [
        1
      ],
      "name": "Chuanlin Zhu"
    },
    {
      "affs": [
        7
      ],
      "name": "Anguo Wu"
    },
    {
      "name": "Ning Jiang"
    },
    {
      "affs": [
        8
      ],
      "name": "Fang Ren"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/adgdxy0vp7byf.bib",
  "cited_by": 0,
  "doi": "10.1016/j.redox.2026.104369",
  "fulltext_url": "http://www.sciencedirect.com/science/article/pii/S221323172600368X",
  "id": "adgdxy0vp7byf",
  "issns": [
    "2213-2317"
  ],
  "landing_url": "https://doi.org/10.1016/j.redox.2026.104369",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "QH301-705.5"
    ],
    [
      "lcc",
      "R5-920"
    ],
    [
      "openalex",
      "2740|Ferroptosis and cancer prognosis"
    ]
  ],
  "openalex": "W7204267564",
  "pdf_url": "https://www.sciencedirect.com/science/article/pii/S221323172600368X/pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-30",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/adgdxy0vp7byf.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:43:15Z",
      "native_id": "639b1e356cc2462aa0372c191df88157",
      "source": "doaj",
      "url": "https://doi.org/10.1016/j.redox.2026.104369"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "journal-openalex:1312|Redox biology and oxidative stress",
      "subfield": "molecular-biology"
    },
    {
      "field": "biology",
      "origin": "lcc:QH301-705.5",
      "subfield": "general"
    },
    {
      "field": "medicine",
      "origin": "lcc:R5-920",
      "subfield": "general"
    }
  ],
  "title": "Cooperative inhibition of mTORC1 disrupts iron–redox homeostasis and triggers ferritinophagy-dependent ferroptosis in hepatocellular carcinoma",
  "title_text": "Cooperative inhibition of mTORC1 disrupts iron–redox homeostasis and triggers ferritinophagy-dependent ferroptosis in hepatocellular carcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:43:15Z",
  "url": "https://research.draconitic.com/paper/adgdxy0vp7byf",
  "venue": "Redox Biology",
  "versions": []
}