SCD1 inhibition blocks the AKT–NRF2–SLC7A11 pathway to induce lipid metabolism remodeling and ferroptosis priming in lung adenocarcinoma Journal Article

   

Authors:	Sen, U.; Coleman, C.; Gandhi, N.; Jethalia, V.; Demircioglu, D.; Elliott, A.; Vanderwalde, A. M.; Hayatt, O.; de Stanchina, E.; Halmos, B.; Ma, P. C.; Berisa, M.; Hasson, D.; Sen, T.
Article Title:	SCD1 inhibition blocks the AKT–NRF2–SLC7A11 pathway to induce lipid metabolism remodeling and ferroptosis priming in lung adenocarcinoma
Abstract:	Concurrent inactivating mutations in STK11 and KEAP1 drive primary resistance to therapies, leading to worse outcomes in KRAS-mutated lung adenocarcinoma (KRASmut LUAD), and are associated with metabolic alterations. Elucidation of the underlying biology of this aggressive LUAD subset is needed to develop effective treatments to improve patient outcomes. Our transcriptomic analysis of 5,498 “real-world” KRASmut LUADs demonstrated that STK11/KEAP1 co-mutation led to upregulation of fatty acid and redox signaling pathways and considerable enrichment of the metabolic genes SCD1 and SLC7A11. High expression of SCD1 and SLC7A11 predicted poor prognosis in KRASmut patients. Transcriptomics, lipidomics, and kinase arrays in preclinical models demonstrated that SCD1 inhibition promoted ferroptosis, altered fatty acid metabolism, and downregulated SLC7A11 via AKT–GSK3β–NRF2 signaling. SCD1 inhibition caused appreciable tumor regression in xenografts and augmented the efficacy of the ferroptosis inducer erastin. Overall, this study provides insights into the role of the SCD1–SLC7A11 axis in regulating metabolic programming and predicting poor patient outcomes in a genetically defined subset of KRASmut LUAD. Significance: SCD1 and SLC7A11 are prognostic biomarkers and therapeutic targets for KRAS/STK11/KEAP1 co-mutant lung adenocarcinoma, which will refocus mechanistic studies and lead to treatment strategies for lung cancer. ©2025 American Association for Cancer Research.
Keywords:	signal transduction; protein kinase b; controlled study; protein expression; protein phosphorylation; treatment outcome; unclassified drug; human cell; genetics; mutation; nonhuman; flow cytometry; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; cell viability; gene; gene expression; tumor volume; lung neoplasms; animal experiment; animal model; tumor regression; drug effect; drug screening; pathology; xenograft model antitumor assays; enzyme inhibitor; cell line, tumor; protein serine threonine kinase; lung tumor; gene expression regulation; gene expression regulation, neoplastic; lung adenocarcinoma; genetic transfection; xenograft; nude mouse; mice, nude; tumor cell line; western blotting; proto-oncogene proteins c-akt; lentivirus; immunoblotting; down regulation; real time polymerase chain reaction; upregulation; drug therapy; protein p21; proto-oncogene proteins p21(ras); lipid peroxidation; lipid metabolism; kras protein, human; rna extraction; adenocarcinoma of lung; rna isolation; euthanasia; stk11 protein, human; acyl coenzyme a desaturase; fatty acid metabolism; transcription factor nrf2; imidazole; cancer prognosis; ferroptosis; kelch like ech associated protein 1; lipidomics; stearoyl-coa desaturase; cell component; humans; prognosis; human; female; article; rna sequencing; amino acid transporter; cell viability assay; crispr-cas9 system; a-549 cell line; nci-h460 cell line; nfe2l2 protein, human; nf-e2-related factor 2; imidazole ketone erastin; acyl coenzyme a desaturase 1; protein serine-threonine kinases; kelch-like ech-associated protein 1; keap1 protein, human; amp-activated protein kinase kinases; hydroxymethylglutaryl coenzyme a reductase kinase kinase; amino acid transport system y+; a939572; stearoyl coa desaturase 1; scd1 protein, human; slc7a11 protein, human; lipid metabolism remodeling; slc7a11 gene
Journal Title:	Cancer Research
Volume:	85
Issue:	13
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2025-07-01
Start Page:	2485
End Page:	2503
Language:	English
DOI:	10.1158/0008-5472.Can-24-2745
PUBMED:	40198901
PROVIDER:	scopus
PMCID:	PMC12221774
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105009920981&doi=10.1158%2f0008-5472.CAN-24-2745&partnerID=40&md5=ec6beaed90f5ed2c93c9481af69296c3
Notes:	Article -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/227214