EGFR/APOC1/CPT1A Axis: A Novel Pathway in Gastric Cancer Metabolism and Its Potential as a Therapeutic Target

Background Gastric cancer (GC) significantly reprograms lipid metabolism for its energy demands, growth, and survival, yet the role of Apolipoprotein C-I (APOC1) in this metabolic reprogramming and its profound implications for GC progression remains unclear. Methods GC cell lines, microarrays and animal models were utilized to examine APOC1 function. Transcriptomic and metabolomic analyses were done to understand the effect of APOC1 overexpressing. The interactions among epidermal growth factor receptor (EGFR), APOC1 and carnitine palmitoyltransferase 1A (CPT1A) were validated using Co-IP, reactive oxygen species, lipid acid oxidation and dual luciferase reporter assay. The combination of EGFR inhibitor and CPT1A inhibitor was tested using a cell-based xenograft model of GC. Results APOC1 is markedly upregulated in GC tissues and cells, correlating with poor patient prognosis. Notably, APOC1 overexpression enhances cancer cell proliferation and migration, while its silencing impairs tumor growth and metastasis. Mechanistically, APOC1 promotes fatty acid oxidation by regulating CPT1A, connecting lipid metabolism directly to tumor dynamics. Disruption of APOC1 leads to metabolic dysregulation and mitochondrial oxidative stress, indicating its critical involvement in cellular homeostasis. Furthermore, the phosphorylation of EGFR was identified as a regulator of APOC1 expression through AP-2α transcription factor binding to its promoter. Targeting the EGFR/APOC1/CPT1A axis inhibits GC progression significantly in vivo . Conclusions This study not only elucidates the intricate EGFR/APOC1/CPT1A signaling axis but also positions APOC1 as a vital target for therapeutic intervention, underscoring its significance in the metabolic landscape of GC. Our findings pave the way for novel strategies aimed at disrupting lipid metabolic pathways in GC treatment.