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

Oncogene volume 45, pages 1386–1397 (2026)Cite this article

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Abstract

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.

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Fig. 1: NPC1 upregulation is correlated with worse prognosis.
Fig. 2: Silencing of NPC1 inhibited tumour cell proliferation in vitro and in vivo.
Fig. 3: NPC1 suppresses p53 expression by enhancing its ubiquitin-dependent degradation.
Fig. 4: NPC1 suppresses p53 expression in a USP7-dependent manner.
Fig. 5: NPC1 regulates the distribution and synthesis of cholesterol in cells.
Fig. 6: Hepatic NPC1 deficiency regulates p53 and cholesterol, limiting HCC progression.

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Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by grants from the Shenzhen Medical Research Funds (A2303050), Shenzhen Science and Technology Innovation Commission Project (JCYJ20250604183742055), Science Technology and Innovation Commission of Shenzhen Municipality (RCBS20210706092253060), Sanming Project of Medicine in Shenzhen (SZSM202411034), Shenzhen Maternity and Child Healthcare Hospital 2022 Annual Research Fund Project (FYA2022011).

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Authors and Affiliations

  1. Department of Radiation Oncology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, Guangdong province, China

    Ru Deng, Feihong Liu, Jing Gao, Ying Li & Yajie Liu

  2. Department of Gastrointestinal surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China

    Xiaoming Zheng

  3. Department of Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen, China

    Shubin Wang

  4. Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China

    Jingping Yun

  5. Key Laboratory of Biological Molecular Medicine Research, Education Department of Guangxi Zhuang Autonomous Region, Guangxi Medical University, Nanning, China

    Feng Wang

  6. Reproductive Medicine Center, Shenzhen Maternity and Child Healthcare Hospital, Women and Children’s Medical Center, Southern Medical University, Shenzhen, Guangdong Province, China

    Xixiong Ai

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  1. Ru Deng
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  2. Xiaoming Zheng
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  10. Yajie Liu
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Contributions

RD, XA, XZ, Y Liu, and JG contributed to the conception and design of the study. RD, XA, FW, and Y Liu developed the methodology. RD, FL, and XA acquired the data. RD, XZ, FL and Y Li performed data analysis and interpretation. RD, XZ, XA, JY, Y Li, SW, and Y Liu contributed to writing, reviewing, and/or revising the manuscript. RD, JY, SW, FW, and Y Liu provided administrative, technical, or material support. RD, XZ, XA, Y Liu, and SW supervised the study.

Corresponding authors

Correspondence to Xixiong Ai or Yajie Liu.

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Deng, R., Zheng, X., Liu, F. et al. The NPC1/USP7/p53 axis regulates cholesterol and promotes the proliferation of hepatocellular carcinoma. Oncogene 45, 1386–1397 (2026). https://doi.org/10.1038/s41388-026-03739-3

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