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

ABSTRACT: Noncanonical metabolic functions of signaling molecules contribute to cancer plasticity and metastatic progression. In this study, we demonstrated that phosphodiesterase type 5A (PDE5A) inhibitors, including sildenafil (Sild; 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 guanosine 3',5'-cyclic monophosphate (cGMP) bound the lysosomal cholesterol transporter NPC1, impairing cholesterol export and phenocopying Niemann-Pick type C pathology. The resulting cholestero

SUBMITTER: Ariav Y 

PROVIDER: S-EPMC13631500 | biostudies-literature | 2026 Oct

REPOSITORIES: biostudies-literature