PDIA6–SCD1 Axis Rewires Lipid Metabolism to Drive Gastric Cancer Progression

ABSTRACT Gastric cancer (GC) remains an aggressive malignancy with limited effective therapeutic options. Integrated single‐cell and bulk transcriptomic analyses identify protein disulfide isomerase A6 (PDIA6) as a tumor epithelial–enriched gene associated with advanced tumor‑ node‑metastasis (TNM) stage and unfavorable survival. Multi‐omics profiling reveals that PDIA6 drives lipid metabolic reprogramming by sustaining the monounsaturated fatty acid (MUFA)–enriched neutral lipid pools required for lipid droplet homeostasis and redox balance. Mechanistically, PDIA6 directly associates with stearoyl‐CoA desaturase 1 (SCD1) through a structure‐defined interface centered on Asp44 of SCD1, thereby restricting its ubiquitin–proteasome–mediated degradation and maintaining SCD1‐dependent 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–stromal interactions may contribute to PDIA6 upregulation, as cancer‐associated fibroblast‐derived C‐X‐C motif chemokine ligand 12 (CXCL12) activated C‐X‐C chemokine receptor 4 (CXCR4)‐dependent signal transducer and activator of transcription 3 (STAT3) signaling in vitro. These findings establish the PDIA6–SCD1 axis as a targetable lipid metabolic dependency in GC and position PDIA6 as a candidate therapeutic vulnerability for precision oncology.