PDE5a Inhibition Restricts Cancer Metastasis by Disrupting NPC1-Mediated Cholesterol Trafficking Through a Non-canonical cGMP-Dependent Pathway.

Abstract

Non-canonical metabolic functions of signaling molecules contribute to cancer plasticity and metastatic progression. Here, we demonstrated that PDE5a inhibitors, including sildenafil (Viagra), induced lysosomal cholesterol accumulation across multiple mouse and human cancer models, reducing cholesterol bioavailability and impairing cancer cell migration and metastasis. Cancer cells exhibited heightened sensitivity due to reduced lysosomal gene expression, rendering them particularly vulnerable to disrupted cholesterol trafficking. Mechanistically, elevated cGMP bound the lysosomal cholesterol transporter NPC1, impairing cholesterol export and phenocopying Niemann-Pick type C pathology. The resulting cholesterol depletion disrupted membrane lipid rafts and mitochondrial bioenergetics, thereby limiting metastatic capacity and triggering compensatory SREBP2 activation with increased cholesterol synthesis. Combining sildenafil with statins yields additive antimetastatic effects by concurrently blocking lysosomal cholesterol export and cholesterol biosynthesis. Consistently, analysis of digital health records demonstrated significantly improved survival among sildenafil users, with a dose-dependent additive benefit observed when combined with statins. Together, these findings identify increasing cGMP levels through PDE5a inhibition as a potential strategy to restrict metastasis and offer a potential mechanistic basis for the beneficial effects of sildenafil.