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Peer-reviewedCC BY 4.0Cell Reports Medicine

L013 promotes NRF2 degradation in NRFA-subtype esophageal squamous cell carcinoma

  • Xiao Yu1
  • Yue Wu2
  • Xiuyun Sun2
  • Rui Han3
  • Yi Cai2
  • Wei Zeng2
  • Yang Li1
  • Yuhao Wang1
  • Yahui Zhao1
  • Yu Rao2
  • Zhihua Liu1,4
4 affiliations
  1. 1State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
  2. 2MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China
  3. 3Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
  4. 4Institute of Cancer Research, Henan Academy of Innovations in Medical Sciences, Zhengzhou, Henan Province 450000, China
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Abstract

NRF2 oncogenic activation (NRFA)-subtype esophageal squamous cell carcinoma (ESCC) patients exhibit poor prognosis and limited response to conventional therapies due to excessive NRF2 protein accumulation. Here, we identify L013, an NRF2 degrader, through high-content screening of 725 cereblon (CRBN) ligand-based degraders. Our results indicate that L013 effectively reduces NRF2 abundance and decreases NFE2L2 mRNA expression in ESCC cells. Mechanistically, L013 promotes NRF2 ubiquitination through a ubiquitin-proteasome system (UPS)-associated process involving Cullin-dependent E3 ligase activity, while its A51-derived scaffold independently contributes to NRF2 suppression, at least in part, by impairing NFE2L2 transcriptional output. In preclinical models, L013 reduces NRF2 levels and suppresses tumor growth in patient-derived organoids (PDOs) of ESCC and lung squamous cell carcinoma (LUSC), as well as ESCC xenograft models. No overt systemic toxicity occurs under the tested dosing regimen. Our findings establish L013 as a promising therapeutic candidate for NRFA-subtype ESCC patients, offering a potential strategy to target NRF2-driven oncogenesis.

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Cite

BibTeXRIS
BibTeX
@article{yu2026l013,
  title = {{L013 promotes NRF2 degradation in NRFA-subtype esophageal squamous cell carcinoma}},
  author = {Xiao Yu and Yue Wu and Xiuyun Sun and Rui Han and Yi Cai and Wei Zeng and Yang Li and Yuhao Wang and Yahui Zhao and Yu Rao and Zhihua Liu},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = sep,
  doi = {10.1016/j.xcrm.2026.103046},
  url = {https://doi.org/10.1016/j.xcrm.2026.103046},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - L013 promotes NRF2 degradation in NRFA-subtype esophageal squamous cell carcinoma
AU  - Xiao Yu
AU  - Yue Wu
AU  - Xiuyun Sun
AU  - Rui Han
AU  - Yi Cai
AU  - Wei Zeng
AU  - Yang Li
AU  - Yuhao Wang
AU  - Yahui Zhao
AU  - Yu Rao
AU  - Zhihua Liu
PY  - 2026
DA  - 2026/09/11
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103046
UR  - https://doi.org/10.1016/j.xcrm.2026.103046
AB  - NRF2 oncogenic activation (NRFA)-subtype esophageal squamous cell carcinoma (ESCC) patients exhibit poor prognosis and limited response to conventional therapies due to excessive NRF2 protein accumulation. Here, we identify L013, an NRF2 degrader, through high-content screening of 725 cereblon (CRBN) ligand-based degraders. Our results indicate that L013 effectively reduces NRF2 abundance and decreases NFE2L2 mRNA expression in ESCC cells. Mechanistically, L013 promotes NRF2 ubiquitination through a ubiquitin-proteasome system (UPS)-associated process involving Cullin-dependent E3 ligase activity, while its A51-derived scaffold independently contributes to NRF2 suppression, at least in part, by impairing NFE2L2 transcriptional output. In preclinical models, L013 reduces NRF2 levels and suppresses tumor growth in patient-derived organoids (PDOs) of ESCC and lung squamous cell carcinoma (LUSC), as well as ESCC xenograft models. No overt systemic toxicity occurs under the tested dosing regimen. Our findings establish L013 as a promising therapeutic candidate for NRFA-subtype ESCC patients, offering a potential strategy to target NRF2-driven oncogenesis.
SN  - 2666-3791
ER  -