{
  "abstract": "Triple-negative breast cancer (TNBC) remains a major clinical challenge due to a lack of effective interventions and severe drug resistance. Disrupting tumor metabolism using nitric oxide (NO) donors to drive ferroptosis represents a promising therapeutic strategy. Here, we developed 3A72, a novel furan-coumarin-based NO donor with potent anti-TNBC efficacy. In vitro and in vivo studies demonstrated that 3A72 significantly suppresses TNBC cell proliferation and restricts xenograft tumor growth. Notably, its efficacy matches the first-line drug paclitaxel but with enhanced safety and reduced systemic toxicity. Mechanistically, 3A72 induces ferroptosis in triple negative breast cancer (TNBC) cells via a synergistic dual-pathway mechanism. Initially, 3A72 releases intracellular NO to trigger cytoplasmic calcium overload, followed by high-affinity binding to both inositol 1,4,5-trisphosphate receptor (IPR) and acyl-CoA synthetase long-chain family member 4 (ACSL4). Binding to IP3R provokes mitochondrial calcium overload and a massive burst of reactive oxygen species (ROS), while concurrent ACSL4 activation drives essential membrane phospholipid remodeling. Crucially, our transcriptomic and structural predictions reveal that while ACSL4 exhibits a broader distribution across organelle membranes, its functional association with IP3R spatially converges at the endoplasmic reticulum membranes associated with mitochondria (MAMs). This subcellular niche closely couples IPR-mediated ROS generation with ACSL4-driven lipid remodeling, accelerating lethal malondialdehyde (MDA) accumulation and triggering irreversible ferroptosis. Overall, these findings highlight the MAMs calcium-lipid metabolic hub as a promising structural scaffold for antitumor drug development.",
  "abstract_shown": true,
  "affiliations": [
    "Fudan University, School of Pharmacy"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "Y. Long"
    },
    {
      "name": "Y. Jiang"
    },
    {
      "name": "L. Li"
    },
    {
      "name": "X. Wu"
    },
    {
      "name": "J. weng"
    },
    {
      "name": "Y. Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "H. Liu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5rkcb85rek53g.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.28.754991",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.28.754991v1.full",
  "id": "5rkcb85rek53g",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.28.754991v1",
  "language": null,
  "licence": "CC-BY-ND",
  "licence_label": "CC BY-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2740|Ferroptosis and cancer prognosis"
    ]
  ],
  "openalex": "W7219648919",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.28.754991v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5rkcb85rek53g.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:57Z",
      "native_id": "10.64898/2026.09.28.754991",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.28.754991v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "A Novel NO Donor 3A72 Activates Mitochondrial-Associated Endoplasmic Reticulum Membrane Structures to Induce Ferroptosis in Triple-Negative Breast Cancer",
  "title_text": "A Novel NO Donor 3A72 Activates Mitochondrial-Associated Endoplasmic Reticulum Membrane Structures to Induce Ferroptosis in Triple-Negative Breast Cancer",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:57Z",
  "url": "https://research.draconitic.com/paper/5rkcb85rek53g",
  "venue": "bioRxiv",
  "versions": []
}