Melittin suppresses ovarian cancer growth by regulating SREBP1-mediated lipid metabolism.

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Melittin, a major peptide component of bee venom, has demonstrated promising anti-cancer activity across various preclinical cell models, making it a potential candidate for cancer therapy. However, its molecular mechanisms, particularly in ovarian cancer, remain largely unexplored. Ovarian cancer is a life-threatening gynecological malignancy with poor clinical outcomes and limited treatment options. This study evaluated the efficacy of melittin in suppressing ovarian cancer and elucidated its underlying molecular mechanisms. A subcutaneous xenograft tumor model was established using ID8 cells in C57BL/6J mice. RNA sequencing revealed that melittin's anticancer effects were associated with the downregulation of lipid metabolism, particularly fatty acid synthesis. The impact of melittin on de novo fatty acid synthesis was assessed by measuring free fatty acid (FFA), triglyceride (TG), and total cholesterol (TC) levels in ovarian cancer cells. Lipogenic gene expression and sterol regulatory element-binding protein 1 (SREBP1) were analyzed by Western blot and quantitative real-time polymerase chain reaction. The regulation of FASN transcription by SREBP1 was explored using a dual-luciferase reporter assay. Plasmid DNA transfection and the SREBP1 inhibitor Fatostatin were employed to identify the signaling pathway mediating melittin's anticancer effects. Our results confirmed that melittin significantly reduced de novo fatty acid synthesis, as evidenced by lower FFA, TG, and lipid droplet levels. Additionally, melittin inhibited the nuclear translocation of SREBP1 and specifically reduced SREBP1-mediated FASN transcription, demonstrating effects similar to those of Fatostatin. The motif (-424/-415) within the FASN promoter is a potential SREBP-1 binding site. SREBP1 overexpression through plasmid DNA transfection significantly counteracted melittin's downregulation of FASN promoter activity and counteracted its inhibitory effects on de novo fatty acid synthesis, cell proliferation, and colony formation. Our findings suggested that melittin acts as a novel modulator of the SREBP1/FASN pathway, reducing lipogenesis and inhibiting ovarian cancer growth. This study was the first to demonstrate melittin's ability to target the SREBP1/FASN axis in ovarian cancer, identifying SREBP1 as a novel therapeutic target. These results highlighted melittin as a potential therapeutic agent for ovarian cancer by attenuating SREBP1-mediated lipid metabolism and suggested novel treatment strategies for targeting ovarian cancer.