{
  "abstract": "Metabolic reprogramming, particularly enhanced lipid anabolism, is a hallmark of oral squamous cell carcinoma (OSCC), yet effective therapies targeting this process remain lacking. Here, we identify concurrent activation of acetyl-CoA synthetase 2 (ACSS2) and ATP-citrate lyase (ACLY) as a cooperative metabolic driver of OSCC progression. Whereas previous efforts have focused on single-enzyme inhibition, we show that ACSS2 and ACLY form a compensatory network that sustains lipid anabolism and drives OSCC progression, providing a rationale for their dual inhibition. Integrative transcriptomic and lipidomic analyses reveal a metabolically aggressive OSCC subset defined by concurrent ACSS2 and ACLY upregulation, which was associated with poor clinical outcomes. Dual inhibition of ACSS2 and ACLY depleted acetyl-CoA, suppressed lipogenesis, and impaired tumor growth in vitro and in vivo. We further identified S8588, a quinoxaline-based small molecule, as a dual-target degrader that induces ubiquitin–proteasome-dependent degradation of both ACSS2 and ACLY, thereby blocking OSCC proliferation. Mechanistically, S8588 directly binds key residues of both enzymes, promoting their proteasomal turnover. Supplementation with acetate and citrate reverses its anti-tumor effect, confirming acetyl-CoA depletion as the primary mechanism. Collectively, our findings establish ACSS2/ACLY co-activation as a therapeutic vulnerability in OSCC and nominate S8588 as a promising dual-target therapeutic to dismantle metabolic adaptability for improved treatment.",
  "abstract_shown": true,
  "affiliations": [
    "Hunan Key Laboratory of Oral Health Research & Hunan Clinical Research Center of Oral Major Diseases and Oral Health & Academician Workstation for Oral-maxilofacial and Regenerative Medicine, Xiangya Stomatological Hospital & Xiangya School of Stomatology, Central South University, Changsha, China",
    "Research Center for Molecular Medicine and Biomanufacturing, Hunan Province Key Laboratory of Basic and Applied Hematology, Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Xiangya School of Medicine, Central South University, Changsha, China",
    "National Clinical Research Center for Geriatric Diseases (Xiangya Hospital), Central South University, Changsha, China",
    "The Oncology Department of Xiangya Second Hospital, Central South University, Changsha, China",
    "The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, China",
    "MOE Key Lab of Rare Pediatric Diseases, Hengyang Medical School, University of South China, Hengyang, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Tiao Luo"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Zhengnan Ming"
    },
    {
      "affs": [
        3
      ],
      "name": "Haixia Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Zizheng Zou"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiyuan Hu"
    },
    {
      "affs": [
        4
      ],
      "name": "Yekui Yin"
    },
    {
      "affs": [
        4
      ],
      "name": "Ying Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Zekun Zhou"
    },
    {
      "affs": [
        0
      ],
      "name": "Xin Bin"
    },
    {
      "affs": [
        0
      ],
      "name": "Jianjun Wu"
    },
    {
      "affs": [
        5
      ],
      "name": "Junli Luo"
    },
    {
      "affs": [
        1
      ],
      "name": "Zhiyong Luo",
      "orcid": "0000-0002-5769-4387"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhangui Tang"
    },
    {
      "affs": [
        0
      ],
      "name": "Ousheng Liu",
      "orcid": "0000-0003-3293-9824"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b10840fmqarc2.bib",
  "cited_by": 0,
  "doi": "10.1038/s41368-026-00467-y",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13723505/",
  "id": "b10840fmqarc2",
  "issns": [
    "1674-2818",
    "2049-3169"
  ],
  "landing_url": "https://doi.org/10.1038/s41368-026-00467-y",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1306|Cancer, Lipids, and Metabolism"
    ]
  ],
  "openalex": "W7224997180",
  "pdf_url": "https://www.nature.com/articles/s41368-026-00467-y.pdf",
  "pmcid": "PMC13723505",
  "pmid": "42966779",
  "published": "2026-10-31",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/b10840fmqarc2.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T12:22:07Z",
      "native_id": "PMC13723505",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41368-026-00467-y"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Cancer, Lipids, and Metabolism",
      "subfield": "oncology"
    }
  ],
  "title": "Dual targeting of ACSS2 and ACLY by a novel inhibitor S8588 suppresses oncogenic lipogenesis and overcomes metabolic compensation in oral squamous cell carcinoma",
  "title_text": "Dual targeting of ACSS2 and ACLY by a novel inhibitor S8588 suppresses oncogenic lipogenesis and overcomes metabolic compensation in oral squamous cell carcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-11-05T12:20:18Z",
  "url": "https://research.draconitic.com/paper/b10840fmqarc2",
  "venue": "International Journal of Oral Science",
  "versions": []
}