PDIA6-SCD1 Axis Rewires Lipid Metabolism to Drive Gastric Cancer Progression.

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.