{
  "abstract": "Triple-negative breast cancer (TNBC) is the most therapeutically challenging breast cancer subtype owing to its aggressive nature and lack of effective targeted therapies. Here, we identify lipase maturation factor 2 (LMF2), a previously uncharacterized gene in human cancer, as a novel oncogenic driver that promotes tumor growth, metastasis, and resistance to capecitabine in TNBC both in vitro and in vivo. Mechanistically, LMF2 localizes predominantly to the endoplasmic reticulum membrane and is targeted for autophagic degradation mediated by the autophagy receptor NBR1. Valosin-containing protein (VCP) counteracts this process to stabilize LMF2 by impeding the LMF2-NBR1 interaction, and pharmacological inhibition of VCP effectively suppressed LMF2-driven TNBC progression and capecitabine resistance. LMF2, in turn, disrupts the interaction between the autophagy receptor NDP52 and HMGCS1, the rate-limiting enzyme in cholesterol biosynthesis, thereby shielding HMGCS1 from autophagic degradation and enhancing cholesterol production. Importantly, re-expression of HMGCS1 or exogenous cholesterol supplementation partially rescued the malignant and chemoresistant phenotypes impaired by LMF2 depletion. Clinically, the VCP-LMF2-HMGCS1 axis is significantly co-upregulated in TNBC patient specimens. Collectively, these findings unveil a previously unrecognized VCP-LMF2-HMGCS1 regulatory axis that drives TNBC progression and chemoresistance, and identify LMF2 as a promising therapeutic target for this recalcitrant disease.",
  "abstract_shown": true,
  "affiliations": [
    "Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.",
    "Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.",
    "Department of Breast and Thyroid Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.",
    "Institutes of Biomedical Sciences, Fudan University, Shanghai, China.",
    "Precision Cancer Medicine Center, Fudan University Shanghai Cancer Center, Shanghai, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Qian Zhao"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Lisa Andriani"
    },
    {
      "affs": [
        0
      ],
      "name": "Yin-Ling Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Shao-Ying Yang",
      "orcid": "0000-0002-1923-9682"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yun-Xiao Ling"
    },
    {
      "affs": [
        3
      ],
      "name": "Min-Ying Huang",
      "orcid": "0009-0006-6374-9969"
    },
    {
      "affs": [
        1
      ],
      "name": "Jia-Yang Cai"
    },
    {
      "affs": [
        0
      ],
      "name": "Fang-Lin Zhang"
    },
    {
      "affs": [
        4
      ],
      "name": "Xin Hu",
      "orcid": "0000-0002-8160-8362"
    },
    {
      "affs": [
        1
      ],
      "name": "A-Yong Cao",
      "orcid": "0009-0004-4652-4683"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zhi-Min Shao",
      "orcid": "0000-0002-4503-148X"
    },
    {
      "affs": [
        1
      ],
      "name": "Guang-Yu Liu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Da-Qiang Li",
      "orcid": "0000-0002-5113-2332"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bbp4she0pc9wt.bib",
  "cited_by": 0,
  "doi": "10.1002/advs.78301",
  "fulltext_url": "https://europepmc.org/articles/PMC13683977",
  "id": "bbp4she0pc9wt",
  "issns": [
    "2198-3844"
  ],
  "landing_url": "https://europepmc.org/article/MED/42902878",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1306|Cancer, Lipids, and Metabolism"
    ]
  ],
  "openalex": "W7223115969",
  "pdf_url": "https://europepmc.org/articles/PMC13683977?pdf=render",
  "pmcid": "PMC13683977",
  "pmid": "42902878",
  "published": "2026-10-20",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/bbp4she0pc9wt.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:53Z",
      "native_id": "MED:42902878",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42902878"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Cancer, Lipids, and Metabolism",
      "subfield": "oncology"
    }
  ],
  "title": "VCP-Regulated LMF2 Stabilizes the Cholesterol Biosynthesis Enzyme HMGCS1 to Drive Cancer Progression and Confer Capecitabine Resistance in Triple-Negative Breast Cancer.",
  "title_text": "VCP-Regulated LMF2 Stabilizes the Cholesterol Biosynthesis Enzyme HMGCS1 to Drive Cancer Progression and Confer Capecitabine Resistance in Triple-Negative Breast Cancer.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:53Z",
  "url": "https://research.draconitic.com/paper/bbp4she0pc9wt",
  "venue": "Advanced science (Weinheim, Baden-Wurttemberg, Germany)",
  "versions": []
}