{
  "abstract": "Sepsis‑associated acute kidney injury (S‑AKI) is a major cause of morbidity and mortality in critically ill patients, yet effective targeted therapies remain lacking due to an incomplete understanding of its pathogenesis. Ferroptosis, an iron‑dependent form of regulated cell death driven by lipid peroxidation, has recently been implicated in AKI, but the upstream regulators of this process in sepsis remain undefined. Here, we identify SIRT5, a mitochondrial NAD ⁺ ‑dependent desuccinylase, as a critical endogenous suppressor of ferroptosis in S‑AKI. Using a cecal ligation and puncture (CLP) murine model and lipopolysaccharide (LPS)‑stimulated HK‑2 proximal tubular cells, we show that SIRT5 expression is significantly downregulated in septic kidney injury. Renal tubular‑specific ablation of Sirt5 exacerbated CLP‑induced renal dysfunction, structural damage, and tubular cell death, whereas AAV9‑mediated SIRT5 overexpression attenuated these pathological changes. Mechanistically, SIRT5 deficiency tipped the balance of the ACSL4/FTH1 axis toward ferroptosis: it increased ACSL4‑dependent membrane lipid remodeling and reduced FTH1‑mediated iron sequestration, accompanied by suppression of the antioxidant enzyme GPX4. Consequently, lipid peroxidation, iron overload, and mitochondrial damage were markedly amplified. Notably, knockdown of ACSL4 in SIRT5‑deficient HK‑2 cells effectively reversed lipid peroxidation, iron accumulation, and cell death, establishing ACSL4 as a key downstream effector of SIRT5‑mediated ferroptosis suppression. Our findings reveal a previously unrecognized SIRT5–ACSL4/FTH1 regulatory axis that governs ferroptotic susceptibility in renal tubular cells during sepsis, and suggest that pharmacological restoration of SIRT5 activity or blockade of ACSL4‑driven ferroptosis may offer novel therapeutic avenues for S‑AKI.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China",
    "Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Liliang Jiang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xi Yu",
      "orcid": "0000-0002-9493-743X"
    },
    {
      "affs": [
        1
      ],
      "name": "Guang Shan"
    },
    {
      "affs": [
        1
      ],
      "name": "Ziqi He"
    },
    {
      "affs": [
        1
      ],
      "name": "Yongbo Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Wenlong Lin"
    },
    {
      "affs": [
        0
      ],
      "name": "Lingling Song"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhongyuan Xia"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/et018py2zb2mw.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pone.0361332",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13712530/",
  "id": "et018py2zb2mw",
  "issns": [
    "1932-6203"
  ],
  "landing_url": "https://doi.org/10.1371/journal.pone.0361332",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Anatomy"
    ],
    [
      "heading",
      "Apoptosis"
    ],
    [
      "heading",
      "Biochemistry"
    ],
    [
      "heading",
      "Bioenergetics"
    ],
    [
      "heading",
      "Bioengineering"
    ],
    [
      "heading",
      "Biology and Life Sciences"
    ],
    [
      "heading",
      "Biotechnology"
    ],
    [
      "heading",
      "Cell Biology"
    ],
    [
      "heading",
      "Cell Death"
    ],
    [
      "heading",
      "Cell Processes"
    ],
    [
      "heading",
      "Cellular Structures and Organelles"
    ],
    [
      "heading",
      "Clinical Medicine"
    ],
    [
      "heading",
      "Energy-Producing Organelles"
    ],
    [
      "heading",
      "Engineering and Technology"
    ],
    [
      "heading",
      "Genetic Engineering"
    ],
    [
      "heading",
      "Genetically Modified Animals"
    ],
    [
      "heading",
      "Genetically Modified Organisms"
    ],
    [
      "heading",
      "Iron Deficiency"
    ],
    [
      "heading",
      "Kidneys"
    ],
    [
      "heading",
      "Lipid Peroxidation"
    ],
    [
      "heading",
      "Lipids"
    ],
    [
      "heading",
      "Medicine and Health Sciences"
    ],
    [
      "heading",
      "Mitochondria"
    ],
    [
      "heading",
      "Nutrition"
    ],
    [
      "heading",
      "Nutritional Deficiencies"
    ],
    [
      "heading",
      "Renal System"
    ],
    [
      "heading",
      "Research Article"
    ],
    [
      "heading",
      "Sepsis"
    ],
    [
      "heading",
      "Signs and Symptoms"
    ],
    [
      "openalex",
      "2727|Acute Kidney Injury Research"
    ],
    [
      "plos",
      "/Biology and life sciences/Anatomy/Renal system/Kidneys"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Bioenergetics/Energy-producing organelles/Mitochondria"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Lipids/Lipid peroxidation"
    ],
    [
      "plos",
      "/Biology and life sciences/Bioengineering/Biotechnology/Genetic engineering/Genetically modified organisms/Genetically modified animals"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cell processes/Cell death"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cell processes/Cell death/Apoptosis"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Cellular structures and organelles/Energy-producing organelles/Mitochondria"
    ],
    [
      "plos",
      "/Biology and life sciences/Nutrition/Nutritional deficiencies/Iron deficiency"
    ],
    [
      "plos",
      "/Engineering and technology/Bioengineering/Biotechnology/Genetic engineering/Genetically modified organisms/Genetically modified animals"
    ],
    [
      "plos",
      "/Medicine and health sciences/Anatomy/Renal system/Kidneys"
    ],
    [
      "plos",
      "/Medicine and health sciences/Clinical medicine/Signs and symptoms/Sepsis"
    ],
    [
      "plos",
      "/Medicine and health sciences/Nutrition/Nutritional deficiencies/Iron deficiency"
    ]
  ],
  "openalex": "W7223951879",
  "pdf_url": "https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0361332&type=printable",
  "pmcid": "PMC13712530",
  "pmid": "42945221",
  "published": "2026-10-27",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/et018py2zb2mw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.1371/journal.pone.0361332",
      "source": "plos",
      "url": "https://doi.org/10.1371/journal.pone.0361332"
    },
    {
      "first_seen": "2026-10-31T12:23:05Z",
      "native_id": "PMC13712530",
      "source": "pmc",
      "url": "https://doi.org/10.1371/journal.pone.0361332"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "heading:Biochemistry",
      "subfield": "general"
    },
    {
      "field": "biology",
      "origin": "plos:cell biology",
      "subfield": "cell-biology"
    },
    {
      "field": "biology",
      "origin": "plos:biotechnology",
      "subfield": "systems-synthetic"
    },
    {
      "field": "medicine",
      "origin": "heading:Nutrition",
      "subfield": "nutrition"
    },
    {
      "field": "medicine",
      "origin": "plos:anatomy",
      "subfield": "physiology"
    }
  ],
  "title": "SIRT5 deficiency exacerbates sepsis acute renal injury by activating ACSL4/FTH1 axis dependent ferroptosis",
  "title_text": "SIRT5 deficiency exacerbates sepsis acute renal injury by activating ACSL4/FTH1 axis dependent ferroptosis",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:23:05Z",
  "url": "https://research.draconitic.com/paper/et018py2zb2mw",
  "venue": "PLOS One",
  "versions": []
}