{
  "abstract": "The BCL-2 protein family controls the intrinsic apoptotic pathway through a delicate balance of pro- and anti-apoptotic members acting at the mitochondrial outer membrane. Anti-apoptotic proteins BCL-2, BCL-XL, MCL-1, BCL-W, and BCL2A1 (BFL-1) function as critical survival factors whose dysregulation contributes to cancer development and therapeutic resistance. This review systematically examines the multilayered regulatory mechanisms governing these proteins, including transcriptional control by NF-κB, STAT3/5, and HIF-1α; post-transcriptional regulation through alternative splicing and microRNAs; and post-translational modifications that determine protein stability and function. The clinical success of venetoclax, a selective BCL-2 inhibitor, has established BCL-2 family targeting as an effective therapeutic strategy and fundamentally changed the management of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, therapeutic challenges persist: resistance emerges through MCL-1 upregulation, BCL-2 mutations, and metabolic reprogramming; BCL-XL inhibition causes dose-limiting thrombocytopenia; and MCL-1 inhibitors face class-wide cardiac toxicity. Emerging strategies to overcome these limitations include tissue-selective proteolysis-targeting chimeras (PROTACs) and antibody-drug conjugates (ADCs) enabling tumor-targeted delivery, next-generation inhibitors that overcome resistance mutations, and biomarker-guided patient selection. This review provides an integrated overview of the regulatory mechanisms and evolving therapeutic strategies targeting anti-apoptotic BCL-2 family proteins, outlining both prominent successes and unresolved challenges.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA",
    "Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA",
    "Immunology Graduate Program, University of Cincinnati, Cincinnati, USA",
    "Department of Oncology and Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA. marina.konopleva@einsteinmed.edu"
  ],
  "article_type": "review",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Zhe Wang",
      "orcid": "0000-0001-5745-7640"
    },
    {
      "affs": [
        1,
        0,
        2
      ],
      "name": "Mutian Tang",
      "orcid": "0009-0008-3204-8689"
    },
    {
      "affs": [
        3
      ],
      "name": "Marina Konopleva",
      "orcid": "0000-0002-9347-2212"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/aa75atxteddrz.bib",
  "cited_by": 10,
  "doi": "10.1038/s41389-026-00632-2",
  "fulltext_url": null,
  "id": "aa75atxteddrz",
  "issns": [
    "2157-9024"
  ],
  "landing_url": "https://doi.org/10.1038/s41389-026-00632-2",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Cell death mechanisms and regulation"
    ]
  ],
  "openalex": "W7163441361",
  "pdf_url": null,
  "pmcid": "PMC13448827",
  "pmid": "42236666",
  "published": "2026-06-03",
  "publisher": "Springer Nature",
  "ris": "https://research.draconitic.com/paper/aa75atxteddrz.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:48Z",
      "native_id": "W7163441361",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41389-026-00632-2"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Cell death mechanisms and regulation",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting",
  "title_text": "Anti-apoptotic BCL-2 family proteins: from regulatory networks to therapeutic targeting",
  "type": "peer-reviewed",
  "updated_at": "2026-11-04T13:21:07Z",
  "url": "https://research.draconitic.com/paper/aa75atxteddrz",
  "venue": "Oncogenesis",
  "versions": []
}