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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Gastric cancer (GC) is an aggressive malignancy with limited treatment options.
• Identifying novel therapeutic targets is crucial for improving patient outcomes.

Purpose of the Study:

• To investigate the role of protein disulfide isomerase A6 (PDIA6) in gastric cancer.
• To elucidate the molecular mechanisms underlying PDIA6 function in GC.
• To evaluate the therapeutic potential of targeting the PDIA6-SCD1 axis.

Main Methods:

• Integrated single-cell and bulk transcriptomic analyses.
• Multi-omics profiling.
• In vivo and in vitro experiments including gene knockdown and drug inhibition.
• Structural analysis of protein-protein interactions.

Main Results:

• PDIA6 is upregulated in GC and associated with advanced TNM stage and poor survival.
• PDIA6 promotes GC progression by reprogramming lipid metabolism, sustaining neutral lipid pools, and maintaining redox balance.
• PDIA6 directly interacts with stearoyl-CoA desaturase 1 (SCD1), inhibiting its degradation and promoting fatty acid desaturation.
• PDIA6 knockdown suppresses tumor growth and metastasis; synergistic inhibition of SCD1 enhances efficacy.
• Tumor-stromal interactions involving CXCL12/CXCR4/STAT3 signaling may upregulate PDIA6.

Conclusions:

• The PDIA6-SCD1 axis represents a critical lipid metabolic dependency in gastric cancer.
• PDIA6 is a potential therapeutic vulnerability for precision oncology in GC treatment.