1.Effects of L013 treatment on gene expression in KYSE150 and KYSE510 cells. 2. 5 Patient-derived organoids RNA-seq data

Here, through high-content screening of 725 CRBN ligand-based PROTACs, we identified L013 as an efficient NRF2 degrader. L013 reduces NRF2 in ESCC cells through dual mechanisms, including ubiquitination-mediated proteasomal degradation and suppression of NRF2 transcription.

Functional studies showed that L013 inhibits the proliferation and tumorigenic capacity of NRF2-hyperactivated ESCC cells. In preclinical models, L013 lowered NRF2 levels and suppressed tumor growth in ESCC or lung squamous cell carcinoma (LUSC) patient-derived organoids and xenograft models, while showing acceptable safety. These findings identify L013 as a promising therapeutic candidate for NRFA-subtype ESCC and support a new strategy for targeting NRF2-driven oncogenesis.