NRP1 Promotes Chronic Lymphocytic Leukemia Progression by Regulating Lipid Synthesis via the EGFR/Akt/SREBP-1 Pathway

Abstract Dysregulated lipid metabolism in chronic lymphocytic leukemia (CLL) correlates strongly with poor prognosis. Neuropilin-1 (NRP1) is upregulated in CLL and implicated in oncogenic signaling, but its role in lipid reprogramming remains unexplored. To investigate whether NRP1 drives CLL progression by regulating lipid synthesis via the EGFR/Akt/SREBP-1 signaling axis. The functional role of NRP1 was investigated in the MEC-1 CLL cell line using siRNA-mediated knockdown and EGFR overexpression strategies. Cellular phenotypes, including proliferation and viability, were quantified using CCK-8 assays, while apoptosis and cell cycle progression were analyzed by flow cytometry. Lipid metabolic alterations were assessed by Oil Red O staining for lipid droplet visualization combined with enzymatic quantification of intracellular triglycerides and total cholesterol. Quantitative real-time PCR (qRT-PCR) facilitated the assessment of transcriptional regulation of lipid synthesis genes, while Western blotting evaluated protein signaling pathways and downstream lipogenic enzyme expression. Knockdown of NRP1 in CLL cells resulted in decreased cell viability and proliferation, as well as apoptosis and G1/S phase arrest. NRP1 knockdown also reduced lipid droplet accumulation and downregulated key lipogenic genes, including ACACA, ACLY, FASN, and SCD-1. Mechanistically, the overexpression of EGFR restored the oncogenic and lipid metabolic abilities of CLL cells compromised by NRP1 deficiency. This study demonstrates that NRP1 promotes CLL progression by activating the EGFR/Akt/SREBP-1 pathway, which drives lipid biosynthesis, suggesting the NRP1/EGFR axis as a potential therapeutic target.