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Integrated single\u2010cell and bulk transcriptomic analyses identify protein disulfide isomerase A6 (PDIA6) as a tumor epithelial\u2013enriched gene associated with advanced tumor\u2011 node\u2011metastasis (TNM) stage and unfavorable survival. Multi\u2010omics profiling reveals that PDIA6 drives lipid metabolic reprogramming by sustaining the monounsaturated fatty acid (MUFA)\u2013enriched neutral lipid pools required for lipid droplet homeostasis and redox balance. Mechanistically, PDIA6 directly associates with stearoyl\u2010CoA desaturase 1 (SCD1) through a structure\u2010defined interface centered on Asp44 of SCD1, thereby restricting its ubiquitin\u2013proteasome\u2013mediated degradation and maintaining SCD1\u2010dependent fatty acid desaturation. In vivo, PDIA6 knockdown suppresses tumor growth and liver metastasis, and synergistic SCD1 inhibition (CAY10566) yields efficacy superior to monotherapies. Upstream, tumor\u2013stromal interactions may contribute to PDIA6 upregulation, as cancer\u2010associated fibroblast\u2010derived C\u2010X\u2010C motif chemokine ligand 12 (CXCL12) activated C\u2010X\u2010C chemokine receptor 4 (CXCR4)\u2010dependent signal transducer and activator of transcription 3 (STAT3) signaling in vitro. These findings establish the PDIA6\u2013SCD1 axis as a targetable lipid metabolic dependency in GC and position PDIA6 as a candidate therapeutic vulnerability for precision oncology.<\/jats:p>","DOI":"10.1002\/advs.75923","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T15:12:13Z","timestamp":1780499533000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PDIA6\u2013SCD1 Axis Rewires Lipid Metabolism to Drive Gastric Cancer Progression"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3759-6368","authenticated-orcid":false,"given":"Zhen","family":"Tian","sequence":"first","affiliation":[{"name":"Northern Jiangsu People's Hospital Clinical Teaching Hospital of Medical School Nanjing University  Yangzhou 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