PDE5A Inhibition Restricts Cancer Metastasis by Disrupting NPC1-Mediated Cholesterol Trafficking through a Noncanonical cGMP-Dependent Pathway.

PDE5a inhibitors like sildenafil reduce cancer metastasis by disrupting NPC1-mediated cholesterol trafficking, causing lysosomal cholesterol accumulation and impairing cell migration.

• Why it matters: Metastasis remains a major challenge in cancer treatment, and understanding how signaling molecules influence cancer plasticity could reveal new therapeutic targets. Disrupting cholesterol trafficking offers a promising approach to limit metastatic progression.
• What they did: The study used multiple mouse and human cancer models to show that PDE5a inhibitors induce lysosomal cholesterol buildup, impairing membrane and mitochondrial functions, and combined sildenafil with statins to enhance anti-metastatic effects.
• The result: This approach significantly decreased metastatic capacity, improved survival outcomes in patients, and suggests that elevating cGMP levels via PDE5a inhibition could be a viable strategy to prevent cancer spread.