SREBP1 is associated with lipid-metabolic reprogramming and apoptotic regulation in pancreatic ductal adenocarcinoma

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and remains associated with limited therapeutic options. Lipid metabolic reprogramming plays a critical role in tumor growth, adaptation to metabolic stress, and therapeutic resistance. However, the role of sterol regulatory element-binding protein 1(SREBP1), encoded by sterol regulatory element-binding transcription factor 1(SREBF1), in apoptosis and lipid-metabolic remodeling in PDAC remains unclear. Methods and Results Public datasets, including The Cancer Genome Atlas (TCGA) and GEPIA, were used to assess the expression and prognostic significance of SREBP1 in PDAC. Differential expression analysis, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and correlation analysis were performed to characterize SREBP1-associated transcriptional and metabolic features. SREBP1 expression was further validated by qRT-PCR and western blotting, and its biological function was evaluated by colony formation and flow cytometric apoptosis assays following gene silencing in pancreatic cancer cells. SREBP1 was significantly upregulated in PDAC and was associated with poor overall survival. Lipid metabolism-related genes, including FASN, were elevated and positively correlated with SREBF1 expression. Transcriptomic and pathway analyses showed that high SREBP1 expression was associated with lipid-metabolic reprogramming, particularly enhanced fatty acid metabolism and cholesterol homeostasis, which was further supported by pathway correlation analyses. Western blot analysis confirmed elevated SREBP1 expression in pancreatic cancer cell lines. Functionally, SREBP1 knockdown suppressed clonogenic growth and significantly increased apoptosis in pancreatic cancer cells. Functionally, SREBP1 knockdown suppressed clonogenic growth and significantly increased apoptosis in pancreatic cancer cells. Conclusion SREBP1-associated lipid-metabolic reprogramming contributes to malignant phenotypes in PDAC. Targeting SREBP1-related metabolic pathways may represent a potential therapeutic strategy for this disease.