{"doi":"10.1016/j.tranon.2025.102629","title":"The PI3K pathway is a downstream effector of NRF2 activation in the esophagus","abstract":"Mutations in nuclear factor erythroid 2–related factor 2 ( NFE2L2 or NRF2 ) occur in 10–22 % of esophageal squamous cell carcinoma (ESCC) cases and result in NRF2 activation, promoting tumor progression, and therapeutic resistance. Although previous studies suggested a link between NRF2 and kinases, specific kinases responsive to NRF2 activation remain to be fully identified. Using protein phosphorylation profiling and kinase activity profiling, we identified phosphatidylinositol 3-kinase (PI3K) pathway as a downstream effector in NRF2 W24C -KYSE70 cells compared to isogenic NRF2 null -KYSE70 cells. AREG, pEGFR, PIK3CA, pAKT, p-S6, and p-PTEN were downregulated in NRF2 deficient cells. Notably, NRF2 deficiency sensitized ESCC cells to EGFR, PIK3CA, and AKT inhibitors. Co-treatment with Alpelisib (a PIK3CA inhibitor) and Pyrimethamine (an NRF2 inhibitor) synergistically suppressed the growth of NRF2 W24C -KYSE70 and NRF2 D77V -KYSE180 cells. In vivo , NRF2 activation in the esophageal epithelium of Keap1 -/- and Sox2CreER;LSL-Nrf2 E79Q/+ mice resulted in upregulation of pAKT, p-mTOR, and pS6. In human ESCC tissues, expression of pNRF2 (an active form of NRF2) was positively associated with that of pAKT and p-mTOR. Furthermore, co-treatment with Pyrimethamine and Alpelisib significantly inhibited hyperproliferation and hyperkeratinization in the esophageal epithelium of Sox2CreER;LSL-Nrf2 E79Q/+ mice. Together, our data demonstrates the PI3K pathway as a downstream effector of NRF2 activation in the esophagus, and co-targeting of NRF2 and the PI3K pathway may offer a promising therapeutic strategy for NRF2 Mut ESCC.","journal":"Translational Oncology","year":2025,"id":583930,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9621,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1140500,"name":"Yahui Li","orcid":"0000-0001-6460-8566","position":1,"is_corresponding":false},{"id":442737,"name":"Zhaohui Xiong","orcid":null,"position":2,"is_corresponding":false},{"id":605083,"name":"Chorlada Paiboonrungruang","orcid":null,"position":3,"is_corresponding":false},{"id":1409624,"name":"Candice Bui-Linh","orcid":null,"position":4,"is_corresponding":false},{"id":1140908,"name":"Francis Spitz","orcid":null,"position":5,"is_corresponding":false},{"id":322817,"name":"Xiaoxin Chen","orcid":"0000-0002-4792-6156","position":6,"is_corresponding":false},{"id":339239,"name":"Boopathi Subramaniyan","orcid":"0000-0003-0243-3777","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:59:07.970345Z","pmid":"41344057","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}