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NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression

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  • Shuangyan Li

    (Tsinghua University
    Beijing Institute of Lifeomics)

  • Lishan Yan

    (Beijing Institute of Lifeomics)

  • Chaoying Li

    (Beijing Institute of Lifeomics)

  • Lijuan Lou

    (Beijing Institute of Lifeomics)

  • Fengjiao Cui

    (Beijing Institute of Lifeomics
    Qingdao University)

  • Xiao Yang

    (Beijing Institute of Lifeomics)

  • Fuchu He

    (Beijing Institute of Lifeomics
    Chinese Academy of Medical Sciences
    Anhui Medical University)

  • Ying Jiang

    (Beijing Institute of Lifeomics
    Anhui Medical University)

Abstract

Niemann-Pick disease type C protein 1 (NPC1), classically associated with cholesterol transport and viral entry, has an emerging role in cancer biology. Here, we demonstrate that knockout of Npc1 in hepatocytes attenuates hepatocellular carcinoma (HCC) progression in both DEN (diethylnitrosamine)-CCl4 induced and MYC-driven HCC mouse models. Mechanistically, NPC1 significantly promotes HCC progression by modulating the TGF-β pathway, independent of its traditional role in cholesterol transport. We identify that the 692-854 amino acid region of NPC1’s transmembrane domain is critical for its interaction with TGF-β receptor type-1 (TGFBR1). This interaction prevents the binding of SMAD7 and SMAD ubiquitylation regulatory factors (SMURFs) to TGFBR1, reducing TGFBR1 ubiquitylation and degradation, thus enhancing its stability. Notably, the NPC1 (P691S) mutant, which is defective in cholesterol transport, still binds TGFBR1, underscoring a cholesterol-independent mechanism. These findings highlight a cholesterol transport-independent mechanism by which NPC1 contributes to the stability of TGFBR1 in HCC and suggest potential therapeutic strategies targeting NPC1 for HCC treatment.

Suggested Citation

  • Shuangyan Li & Lishan Yan & Chaoying Li & Lijuan Lou & Fengjiao Cui & Xiao Yang & Fuchu He & Ying Jiang, 2025. "NPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55788-5
    DOI: 10.1038/s41467-024-55788-5
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