{
  "abstract": "Non-small cell lung cancer (NSCLC) is molecularly heterogeneous, and computationally nominated biomarkers often lack sufficient functional validation. CALB1 is a calcium-binding protein, but its clinical relevance, cellular source, and signaling role in NSCLC remain unclear. This study aimed to identify subtype-associated regulators in NSCLC through a machine-learning-assisted multi-omics framework and to characterize the functional and signaling relevance of CALB1 in malignant progression. NSCLC transcriptomic cohorts were used to define metabolic-epigenetic remodeling (MER) subtypes. Machine-learning-assisted Cox modeling was then applied to identify subtype-associated prognostic regulators. CALB1 was selected for further validation using public cohorts, in-house NSCLC specimens, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry, single-cell RNA sequencing, proteomic and phosphoproteomic profiling, and functional assays. CALB1 was silenced in A549 and PC9 cells to assess its effects on PI3K/AKT activation, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT)-associated phenotypes. Alpelisib was used as a PI3Kα inhibitor to examine the pathway-level involvement of PI3K/AKT signaling in CALB1-associated phenotypes. In vivo relevance and alpelisib responsiveness were further evaluated using a four-group subcutaneous A549 xenograft model comprising sh-Control + vehicle, sh-CALB1 + vehicle, sh-Control + alpelisib, and sh-CALB1 + alpelisib groups. Three MER subtypes were identified, with MER2 showing the poorest prognosis and distinct immune-metabolic features. CALB1 was retained in the prognostic model and positively correlated with model-derived risk scores. CALB1 was upregulated in NSCLC tissues, associated with advanced clinicopathological features and unfavorable prognosis, and mainly enriched in malignant epithelial cells. CALB1-high tumors showed enrichment of proliferative, metabolic, DNA repair, and PI3K/AKT-related programs. CALB1 knockdown induced coordinated proteomic and phosphoproteomic changes involving proliferation, migration, extracellular matrix organization, secretory trafficking, and PI3K/AKT signaling. Functionally, CALB1 silencing reduced p-PI3K and p-AKT levels and suppressed proliferation, migration, invasion, and EMT-associated phenotypes. PI3Kα inhibition with alpelisib attenuated CALB1 overexpression-associated malignant phenotypes in vitro. In vivo, stable CALB1 knockdown suppressed xenograft growth and enhanced the antitumor response to alpelisib, with the sh-CALB1 + alpelisib group showing the greatest reductions in tumor volume and tumor weight. This study identifies CALB1 as a subtype-associated regulator in NSCLC through a machine-learning-assisted multi-omics framework. CALB1 may promote malignant progression partly through PI3K/AKT-related signaling. Stable CALB1 knockdown increased the in vivo antitumor response to alpelisib, supporting CALB1 as a potential modulator of PI3Kα inhibitor sensitivity.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.",
    "Department of Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Feng Mao"
    },
    {
      "affs": [
        1
      ],
      "name": "Ning Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yuming Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Ziang Wang"
    },
    {
      "affs": [
        1
      ],
      "name": "Hui Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Qingquan Luo"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/33gxadepsy7nr.bib",
  "cited_by": 0,
  "doi": "10.21037/tlcr-2026-0576",
  "fulltext_url": "https://europepmc.org/articles/PMC13743441",
  "id": "33gxadepsy7nr",
  "issns": [
    "2218-6751",
    "2226-4477"
  ],
  "landing_url": "https://europepmc.org/article/MED/42999431",
  "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": [
    [
      "openalex",
      "2740|Lung Cancer Treatments and Mutations"
    ]
  ],
  "openalex": "W7223885460",
  "pdf_url": "https://europepmc.org/articles/PMC13743441?pdf=render",
  "pmcid": "PMC13743441",
  "pmid": "42999431",
  "published": "2026-09-29",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/33gxadepsy7nr.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:41Z",
      "native_id": "MED:42999431",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42999431"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "journal-openalex:2730|Lung Cancer Research Studies",
      "subfield": "oncology"
    }
  ],
  "title": "Machine-learning-assisted multi-omics profiling identifies CALB1 as a subtype-associated regulator of PI3K/AKT signaling and malignant progression in non-small cell lung cancer.",
  "title_text": "Machine-learning-assisted multi-omics profiling identifies CALB1 as a subtype-associated regulator of PI3K/AKT signaling and malignant progression in non-small cell lung cancer.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T15:20:41Z",
  "url": "https://research.draconitic.com/paper/33gxadepsy7nr",
  "venue": "Translational lung cancer research",
  "versions": []
}