{
  "abstract": "Liver fibrosis is a pressing clinical challenge, poses a huge threat to human health. However, there is no approved therapeutic medication to treat this devastating disease. Using a drug repositioning or drug rescue (DDDR) strategy, we identified the anti-analgesic agent flupirtine as a potential anti-liver fibrosis candidate through cell-based high-throughput screening of the FDA-approved drug library. Treatment with flupirtine reversed TGF-β1-induced fibrogenesis and ameliorated liver fibrosis in CCl4 or DDC diet-treated fibrotic mice. Asparagine synthase (ASNS) was identified as the direct target of flupirtine. Flupirtine interacted with the residues Asp 401 and Arg 404 of ASNS, thereby inhibiting its enzymatic activity. Importantly, ASNS levels were increased in activated hepatic stellate cells (acHSCs) and in the livers of fibrotic mice and humans, and are positively correlated with the severity of liver fibrosis. Mechanistically, inhibition or deletion of ASNS to increase l-aspartate levels reversed TGF-β1-induced Ca2+ overload in mitochondria, leading to suppression of calpain 1/complex I/mitochondrial reactive oxygen species (mtROS) axis, thereby improving mitochondrial quality and enhancing mitochondrial oxidation, ultimately counteracting liver fibrosis. Our study identified ASNS as a potential therapeutic target for treating liver fibrosis, flupirtine counteracted liver fibrosis in mice by suppressing ASNS in acHSCs, thereby blocking mitochondrial Ca2+/calpain 1/complex I/mtROS axis.",
  "abstract_shown": true,
  "affiliations": [
    "Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570100, China",
    "Guangdong Provincial Key Laboratory of New Drug Screening, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China",
    "School of Chemistry and Chemical Engineering and Guangdong Cosmetics Engineering and Technology Research Center, Guangdong Pharmaceutical University, Zhongshan 528458, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 14,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yong Rao"
    },
    {
      "affs": [
        0
      ],
      "name": "Rui Su"
    },
    {
      "affs": [
        0
      ],
      "name": "Huiling Fu"
    },
    {
      "affs": [
        0
      ],
      "name": "Jin Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenjie Cao"
    },
    {
      "affs": [
        1
      ],
      "name": "Zichao Yang"
    },
    {
      "affs": [
        2
      ],
      "name": "Chen Zhang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaoxuan Su"
    },
    {
      "affs": [
        0
      ],
      "name": "Feifei Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhongping Jiang"
    },
    {
      "affs": [
        0
      ],
      "name": "Congjun Xu"
    },
    {
      "affs": [
        0
      ],
      "name": "Wandi Xiong"
    },
    {
      "affs": [
        0
      ],
      "name": "Haibin Luo"
    },
    {
      "affs": [
        0
      ],
      "name": "Ling Huang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dgt24p3bgm2g1.bib",
  "cited_by": 0,
  "doi": "10.1016/j.apsb.2026.08.017",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13729717/?tool=EBI",
  "id": "dgt24p3bgm2g1",
  "issns": [
    "2211-3835",
    "2211-3843"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13729717",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Article"
    ],
    [
      "openalex",
      "2721|Liver physiology and pathology"
    ]
  ],
  "openalex": "W7203875151",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13729717/pdf/?tool=EBI",
  "pmcid": "PMC13729717",
  "pmid": "42979452",
  "published": "2026-08-21",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/dgt24p3bgm2g1.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T15:20:47Z",
      "native_id": "PMC:PMC13729717",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13729717"
    },
    {
      "first_seen": "2026-11-07T12:22:28Z",
      "native_id": "PMC13729717",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.apsb.2026.08.017"
    }
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2721|Liver physiology and pathology",
      "subfield": "general"
    }
  ],
  "title": "Identification of flupirtine as a candidate against liver fibrosis in mice: Preserving mitochondria quality by suppressing calpain 1/complex I/mtROS axis via targeting asparagine synthase",
  "title_text": "Identification of flupirtine as a candidate against liver fibrosis in mice: Preserving mitochondria quality by suppressing calpain 1/complex I/mtROS axis via targeting asparagine synthase",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:22:28Z",
  "url": "https://research.draconitic.com/paper/dgt24p3bgm2g1",
  "venue": "Acta pharmaceutica Sinica. B",
  "versions": []
}