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

Esophageal squamous cell carcinoma (ESCC) patients with the NRF2 oncogenic activation (NRFA) subtype have poor prognosis and limited response to conventional therapies due to excessive NRF2 accumulation. 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.