{
  "abstract": "Juvenile sepsis-associated brain injury (SABI) lacks effective targeted therapies, and ferroptosis has emerged as a critical pathogenic mechanism. N⁶-methyladenosine (m⁶A) modification is increasingly recognized as a key epitranscriptomic regulator in inflammatory and neurological disorders, yet its role in ferroptosis regulation during SABI remains unexplored. Here, we identify a novel METTL3-PCBP1-ferroptosis axis that drives hippocampal neuronal injury in SABI. Using a cecal ligation and puncture (CLP)-induced rat SABI model and an in vitro co-culture system of lipopolysaccharide (LPS)-stimulated microglia with primary hippocampal neurons, we demonstrate that SABI significantly upregulates methyltransferase-like 3 (METTL3) expression and global m⁶A modification levels in the hippocampus. MeRIP-seq reveals that poly(rC)-binding protein 1 (Pcbp1) mRNA-encoding an iron chaperone that maintains cellular iron homeostasis-exhibits the most pronounced increase in m⁶A modification among cell death-related genes, with site-specific methylation at position 1151 (GGACA motif). This modification recruits the m⁶A reader YTH domain-containing family protein 2 (YTHDF2), promoting Pcbp1 mRNA decay and subsequent PCBP1 protein downregulation. Loss of PCBP1 reduces glutathione peroxidase 4 (GPX4) expression-likely through impaired mRNA binding-and disrupts intracellular Fe²⁺ homeostasis, ultimately triggering ferroptosis characterized by lipid peroxidation and mitochondrial damage. Notably, METTL3 knockdown restores PCBP1 expression, normalizes Fe²⁺ levels, upregulates GPX4, and attenuates ferroptosis and hippocampal injury; however, concurrent PCBP1 knockdown reverses these protective effects. Furthermore, PCBP1 overexpression in SABI rats rescues ferroptosis and neurological deficits. Collectively, our findings establish that METTL3-mediated m⁶A modification of Pcbp1 mRNA exacerbates ferroptosis and SABI pathogenesis, identifying the METTL3/PCBP1 axis as a promising therapeutic target for juvenile SABI.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Emergency, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.",
    "Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China.",
    "Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.",
    "Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, 610041, China. qiaolina@scu.edu.cn.",
    "Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. qiaolina@scu.edu.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Fajuan Tang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Hu Gao"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Bin Chen"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Junjie Ning"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Min Yang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xihong Li"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Lina Qiao",
      "orcid": "0000-0002-2866-2124"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7s9bm3gppx6nk.bib",
  "cited_by": 0,
  "doi": "10.1007/s10565-026-10239-3",
  "fulltext_url": "https://europepmc.org/articles/PMC13719855",
  "id": "7s9bm3gppx6nk",
  "issns": [
    "0742-2091",
    "1573-6822"
  ],
  "landing_url": "https://europepmc.org/article/MED/42957911",
  "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",
      "Research"
    ],
    [
      "openalex",
      "1312|RNA modifications and cancer"
    ]
  ],
  "openalex": "W7172275114",
  "pdf_url": "https://europepmc.org/articles/PMC13719855?pdf=render",
  "pmcid": "PMC13719855",
  "pmid": "42957911",
  "published": "2026-08-03",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7s9bm3gppx6nk.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T00:20:47Z",
      "native_id": "MED:42957911",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42957911"
    },
    {
      "first_seen": "2026-11-02T12:23:45Z",
      "native_id": "PMC13719855",
      "source": "pmc",
      "url": "https://doi.org/10.1007/s10565-026-10239-3"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA modifications and cancer",
      "subfield": "molecular-biology"
    }
  ],
  "title": "METTL3-mediated m⁶A modification targets the regulation of PCBP1 expression, thereby modulating GPX4 levels and intracellular Fe²⁺ homeostasis to influence ferroptosis and contribute to juvenile sepsis-associated brain injury.",
  "title_text": "METTL3-mediated m⁶A modification targets the regulation of PCBP1 expression, thereby modulating GPX4 levels and intracellular Fe²⁺ homeostasis to influence ferroptosis and contribute to juvenile sepsis-associated brain injury.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:50Z",
  "url": "https://research.draconitic.com/paper/7s9bm3gppx6nk",
  "venue": "Cell biology and toxicology",
  "versions": []
}