{
  "abstract": "Environmental hypoxia is a major yet mechanistically unresolved driver of male infertility. While the canonical hypoxia-inducible factor (HIF) and reactive oxygen species (ROS) pathways dominate current models, how chronic oxygen deprivation persistently rewires spermatogenic epigenetics and flagellar architecture remains unknown. Here, we identify CEP162-traditionally defined as a static ciliary transition zone scaffold-as a dynamic oxygen-sensitive signaling hub that orchestrates a pathogenic metabolic-epigenetic-trafficking axis. In human asthenozoospermia and murine hypoxia models, CEP162 is aberrantly upregulated and strongly correlates with flagellar malformation and motility loss. Mechanistically, hypoxia inhibits succinate dehydrogenase, driving the accumulation of intracellular succinate, which disrupts the DNA methyltransferase 3-like (DNMT3L)-additional sex combs-like 2 (ASXL2) epigenetic repressor complex in a HIF-independent manner. This triggers CEP162 promoter hypomethylation and transcriptional derepression, establishing a stable epigenetic switch. Functionally, elevated levels of CEP162 act as a dominant negative regulator of ciliary protein delivery: biolayer interferometry and nucleotide exchange assays revealed that CEP162 spatially sequesters Rab1a and noncompetitively inhibits TRAPPC9-mediated GTP loading, thereby uncoupling vesicular trafficking from axonemal cargo delivery. Consequently, TEKT2 is not incorporated into the growing flagellum, leading to microtubule doublet destabilization and structural collapse. Genetic silencing of CEP162 or restoration of DNMT3L/ASXL2 activity fully rescues Rab1a activation, vesicular targeting, and sperm motility. Clinically, sperm CEP162 levels showed promising diagnostic potential in our initial cohort (area under the curve [AUC] >0.9) and were inversely correlated with progressive motility. This study redefines CEP162 from a passive structural component to an active metabolic-epigenetic sensor, reveals a noncanonical mechanism of Rab guanosine triphosphatase (GTPase) regulation and establishes a reversible succinate-driven epigenetic trajectory in environmentally induced infertility. These findings provide a mechanistic framework for metabolic-epigenetic coupling in polarized cells, identify actionable targets for environmentally induced male infertility and highlight a pathogenic axis that may warrant further investigation in the context of broader ciliopathies.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pathophysiology, Army Medical University, Chongqing 400038, China.",
    "Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing 400038, China.",
    "Key Laboratory of High Altitude Medicine, PLA, Chongqing 400038, China.",
    "Department of High Altitude Operational Medicine, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China.",
    "Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.",
    "Department of Frigid Zone Medicine, College of High Altitude Military Medicine, Army Medical University, Chongqing 400038, China.",
    "The Clinical Research Center, Southwest Hospital, Army Medical University, Chongqing 400038, China.",
    "Department of Obstetrics and Gynecology, Daping Hospital, Army Medical University, Chongqing 400042, China.",
    "Reproductive Medical Center, Southwest Hospital, Army Medical University, Chongqing 400038, China."
  ],
  "article_type": "research support, non u.s. gov't",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Jun Yin"
    },
    {
      "affs": [
        3
      ],
      "name": "Zhifeng Zhong"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Mengjie Zhang"
    },
    {
      "affs": [
        4
      ],
      "name": "Debao Li"
    },
    {
      "affs": [
        5
      ],
      "name": "Aiping Wang"
    },
    {
      "affs": [
        6
      ],
      "name": "Qianying Huang"
    },
    {
      "affs": [
        7
      ],
      "name": "Qinghua Zhang"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Bing Ni"
    },
    {
      "affs": [
        8
      ],
      "name": "Wei He"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/faarspq0m3tke.bib",
  "cited_by": 0,
  "doi": "10.7150/ijbs.137355",
  "fulltext_url": "https://europepmc.org/articles/PMC13686052",
  "id": "faarspq0m3tke",
  "issns": [
    "1449-2288"
  ],
  "landing_url": "https://europepmc.org/article/MED/42910280",
  "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",
      "1312|Epigenetics and DNA Methylation"
    ]
  ],
  "openalex": "W7221441457",
  "pdf_url": "https://europepmc.org/articles/PMC13686052?pdf=render",
  "pmcid": "PMC13686052",
  "pmid": "42910280",
  "published": "2026-10-09",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/faarspq0m3tke.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:10Z",
      "native_id": "MED:42910280",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42910280"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Epigenetics and DNA Methylation",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Hypoxia Reprograms a Ciliary Scaffold into a Metabolic-Epigenetic Trafficking Hub via a Succinate-Driven DNMT3L-ASXL2 Axis.",
  "title_text": "Hypoxia Reprograms a Ciliary Scaffold into a Metabolic-Epigenetic Trafficking Hub via a Succinate-Driven DNMT3L-ASXL2 Axis.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:10Z",
  "url": "https://research.draconitic.com/paper/faarspq0m3tke",
  "venue": "International journal of biological sciences",
  "versions": []
}