{
  "abstract": "Proteasome inhibitor drugs are currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. These inhibitors cause accumulation of undegraded proteins, thus inducing proteotoxic stress and consequent cell death. However, cancer cells counteract this effect by activating an adaptive response through the transcription factor Nuclear factor erythroid 2-related factor 1 (NRF1, also known as NFE2L1). NRF1 induces transcriptional upregulation of proteasome and autophagy/lysosomal genes, thereby reducing proteotoxic stress and diminishing the effectiveness of proteasome inhibition. While suppressing this protective autophagy response is one potential strategy, here we investigated whether this heightened autophagy could instead be leveraged therapeutically. To this end, we designed an autophagy-targeting chimera (AUTAC) compound to selectively degrade the anti-apoptotic protein Mcl1 via the lysosome. Our results show that this lysosome-mediated targeted degradation is significantly amplified in the presence of proteasome inhibition, in a NRF1-dependent manner. The combination of the proteasome inhibitor carfilzomib and Mcl1 AUTAC synergistically promoted cell death in both wild-type and proteasome inhibitor-resistant multiple myeloma and lung cancer cells. Thus, our work offers a novel strategy for enhancing proteasome inhibitor efficacy by exploiting the adaptive autophagy response. More broadly, our study establishes a framework for amplifying lysosome-mediated targeted protein degradation, with potential applications in cancer therapeutics and beyond.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA",
    "Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt",
    "Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA",
    "Virginia Commonwealth University",
    "Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA, USA",
    "Division of Hematology and Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA",
    "Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA",
    "Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA",
    "Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA. Senthil.Radhakrishnan@vcuhealth.org",
    "Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. Senthil.Radhakrishnan@vcuhealth.org"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0,
        1,
        2,
        3
      ],
      "name": "Ahmed M. Elshazly",
      "orcid": "0000-0003-0353-1643"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Nayyerehalsadat Hosseini",
      "orcid": "0000-0003-0443-9371"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Janakiram Vangala"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Shanwei Shen",
      "orcid": "0000-0002-7701-4406"
    },
    {
      "affs": [
        4,
        3
      ],
      "name": "Victoria L. Neely",
      "orcid": "0009-0004-8409-1823"
    },
    {
      "affs": [
        5,
        6,
        3
      ],
      "name": "Xiaoyan Hu"
    },
    {
      "affs": [
        7,
        3
      ],
      "name": "Piyusha P. Pagare"
    },
    {
      "affs": [
        6,
        4
      ],
      "name": "Hisashi Harada",
      "orcid": "0000-0001-5993-1289"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Steven Grant",
      "orcid": "0000-0003-4452-9320"
    },
    {
      "affs": [
        8,
        9
      ],
      "name": "Senthil K. Radhakrishnan",
      "orcid": "0000-0002-5211-9498"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/080rr44mna5tj.bib",
  "cited_by": 7,
  "doi": "10.1038/s41419-026-08835-6",
  "fulltext_url": null,
  "id": "080rr44mna5tj",
  "issns": [
    "2041-4889"
  ],
  "landing_url": "https://doi.org/10.1038/s41419-026-08835-6",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W4407078329",
  "pdf_url": null,
  "pmcid": "PMC11838415",
  "pmid": "39974947",
  "published": "2026-05-11",
  "publisher": "Springer Nature",
  "ris": "https://research.draconitic.com/paper/080rr44mna5tj.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:48Z",
      "native_id": "W4407078329",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41419-026-08835-6"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Proteasome inhibition enhances lysosome-mediated targeted protein degradation",
  "title_text": "Proteasome inhibition enhances lysosome-mediated targeted protein degradation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T13:20:30Z",
  "url": "https://research.draconitic.com/paper/080rr44mna5tj",
  "venue": "Cell Death and Disease",
  "versions": []
}