The NPC1/USP7/p53 axis regulates cholesterol and promotes the proliferation of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally; however, the molecular drivers remain unclear. Dysregulated cholesterol metabolism is a hallmark of HCC and contributes to tumor progression. The Niemann-Pick type C1 protein (NPC1), a lysosomal cholesterol transporter, is overexpressed in cancers; however, its oncogenic mechanisms in HCC remain unclear. In this study, we identified NPC1 as a critical regulator of HCC progression through dual mechanisms involving p53 destabilization and modulation of cholesterol metabolism. Analysis of the clinical data revealed that NPC1 was significantly upregulated in HCC tissues and correlated with poor prognosis. Functional studies have demonstrated that NPC1 silencing suppresses HCC cell proliferation, both in vitro and in vivo. Mechanistically, NPC1 interacts with deubiquitinase ubiquitin-specific protease 7 (USP7), disrupting its binding to p53 and enhancing p53 ubiquitination and proteasomal degradation. Concurrently, NPC1 modulates cholesterol synthesis and distribution via the p53-SREBP2 axis, and p53 knockdown reverses the cholesterol reduction caused by NPC1 silencing. The pharmacological activation of p53 reversed the decrease in cholesterol levels mediated by the overexpression of NPC1. These findings reveal that NPC1 is a multifaceted oncoprotein in HCC, linking cholesterol metabolism to p53 regulation and highlighting its potential as a therapeutic target for HCC intervention.