{
  "abstract": "Introduction\n\nThe molecular chaperone HSPA8 is classically recognized for its role in protein homeostasis, and while its upregulation correlates with poor prognosis in triple-negative breast cancer (TNBC), whether HSPA8 exerts non-canonical functions beyond chaperoning remains unknown.Methods\n\nThrough integrative transcriptomic profiling, RNA immunoprecipitation (RIP), isoform-specific rescue experiments, and in vivo xenograft models, we investigated the functional and mechanistic role of HSPA8 in TNBC pathogenesis.Results\n\nWe unveil a paradigm-shifting function for HSPA8 as a modulator of alternative splicing of the PP2A regulatory subunit gene PPP2R2D, promoting exon 2 retention to favor the full-length PPP2R2D-2 isoform over the truncated PPP2R2D-1. These two isoforms exhibit functionally distinct roles: only PPP2R2D-2 possesses pro-survival activity, whereas PPP2R2D-1 lacks this function. Specifically, PPP2R2D-2 rescues HSPA8 depletion-induced apoptosis by modulating the mitochondrial pathway (BAX/BCL-2/cleaved Caspase-3) and restores in vivo tumor growth. Strikingly, this splicing axis also correlates with an immunosuppressive tumor microenvironment, characterized by altered M1/M2 macrophage marker abundance.Discussion\n\nThese findings uncover a dual mechanism that simultaneously drives intrinsic survival signaling and is associated with alterations in the tumor immune microenvironment. They transcend the classical chaperone paradigm by establishing HSPA8 as a non-canonical splicing modulator, and the HSPA8-PPP2R2D-2 axis emerges as a critical vulnerability in TNBC, offering a novel therapeutic angle that concurrently targets tumor cell survival and microenvironmental immunosuppression.",
  "abstract_shown": true,
  "affiliations": [
    "Breast Surgery Department, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Wenting Xu"
    },
    {
      "affs": [
        0
      ],
      "name": "Qingwen Zheng"
    },
    {
      "affs": [
        0
      ],
      "name": "Yu Si"
    },
    {
      "affs": [
        0
      ],
      "name": "Tian Yao"
    },
    {
      "affs": [
        0
      ],
      "name": "Hao Lei"
    },
    {
      "affs": [
        0
      ],
      "name": "Yongtao Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4k93dqgxdksk2.bib",
  "cited_by": 0,
  "doi": "10.3389/fonc.2026.1941438",
  "fulltext_url": "https://europepmc.org/articles/PMC13677496",
  "id": "4k93dqgxdksk2",
  "issns": [
    "2234-943X"
  ],
  "landing_url": "https://europepmc.org/article/MED/42898301",
  "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|RNA Research and Splicing"
    ]
  ],
  "openalex": "W7219804706",
  "pdf_url": "https://europepmc.org/articles/PMC13677496?pdf=render",
  "pmcid": "PMC13677496",
  "pmid": "42898301",
  "published": "2026-10-05",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/4k93dqgxdksk2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:37Z",
      "native_id": "MED:42898301",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42898301"
    },
    {
      "first_seen": "2026-10-30T12:20:13Z",
      "native_id": "10.3389/fonc.2026.1941438",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fonc.2026.1941438/full"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|RNA Research and Splicing",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Beyond chaperoning: HSPA8 modulates alternative splicing of PPP2R2D to drive apoptotic evasion and macrophage-associated immune microenvironment remodeling in triple-negative breast cancer.",
  "title_text": "Beyond chaperoning: HSPA8 modulates alternative splicing of PPP2R2D to drive apoptotic evasion and macrophage-associated immune microenvironment remodeling in triple-negative breast cancer.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:13Z",
  "url": "https://research.draconitic.com/paper/4k93dqgxdksk2",
  "venue": "Frontiers in oncology",
  "versions": []
}