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Peer-reviewedCC BYCell Death and Disease

Proteasome inhibition enhances lysosome-mediated targeted protein degradation

  • Ahmed M. Elshazly1,2,3,4
  • Nayyerehalsadat Hosseini1,4
  • Janakiram Vangala1,4
  • Shanwei Shen1,4
  • Victoria L. Neely5,4
  • Xiaoyan Hu6,7,4
  • Piyusha P. Pagare8,4
  • Hisashi Harada7,5
  • Steven Grant6,7
  • Senthil K. Radhakrishnan9,10
10 affiliations
  1. 1Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA
  2. 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt
  3. 3Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA
  4. 4Virginia Commonwealth University
  5. 5Philips Institute for Oral Health Research, School of Dentistry, Virginia Commonwealth University, Richmond, VA, USA
  6. 6Division of Hematology and Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
  7. 7Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
  8. 8Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
  9. 9Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA. [email protected]
  10. 10Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA. [email protected]
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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.

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Cite

BibTeXRIS
BibTeX
@article{elshazly2026proteasome,
  title = {{Proteasome inhibition enhances lysosome-mediated targeted protein degradation}},
  author = {Ahmed M. Elshazly and Nayyerehalsadat Hosseini and Janakiram Vangala and Shanwei Shen and Victoria L. Neely and Xiaoyan Hu and Piyusha P. Pagare and Hisashi Harada and Steven Grant and Senthil K. Radhakrishnan},
  journal = {Cell Death and Disease},
  year = {2026},
  month = may,
  doi = {10.1038/s41419-026-08835-6},
  url = {https://doi.org/10.1038/s41419-026-08835-6},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Proteasome inhibition enhances lysosome-mediated targeted protein degradation
AU  - Ahmed M. Elshazly
AU  - Nayyerehalsadat Hosseini
AU  - Janakiram Vangala
AU  - Shanwei Shen
AU  - Victoria L. Neely
AU  - Xiaoyan Hu
AU  - Piyusha P. Pagare
AU  - Hisashi Harada
AU  - Steven Grant
AU  - Senthil K. Radhakrishnan
PY  - 2026
DA  - 2026/05/11
JO  - Cell Death and Disease
DO  - 10.1038/s41419-026-08835-6
UR  - https://doi.org/10.1038/s41419-026-08835-6
AB  - 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.
SN  - 2041-4889
ER  -