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

PDE5A inhibitors, including sildenafil, induce lysosomal cholesterol accumulation and reduce metastasis in cancer models by disrupting NPC1-mediated cholesterol trafficking.

• Why it matters: Understanding how signaling molecules influence cancer plasticity and metastasis can reveal new therapeutic strategies; current knowledge of cholesterol trafficking's role in metastasis is limited.
• What they did: Researchers used multiple mouse and human cancer models to show that PDE5A inhibitors cause lysosomal cholesterol buildup, impairing cell migration and metastasis, and combined sildenafil with statins to enhance effects.
• The result: Findings suggest that increasing cGMP levels via PDE5A inhibition can restrict metastasis by disrupting cholesterol trafficking, with clinical data indicating improved survival in sildenafil users, especially when combined with statins.