NPC1 as a novel therapeutic target for induction of pyroptosis in cancers.

IF 11.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomarker Research Pub Date : 2025-09-26 DOI:10.1186/s40364-025-00823-w

Chuanchao Zhang, Qiang Wang, Pan Su, Jianfei Qian, Qi Guo, Wei Wu, Rui Duan, Yufei Zhang, Youli Zu, Ling Zhong, Liuling Xiao, Qing Yi

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引用次数: 0

Abstract

Background: Cholesterol metabolism reprogramming is a hallmark of cancer cells that exhibit cholesterol addiction by absorbing low-density lipoprotein (LDL) to generate cholesterol for growth. Yet the underlying mechanisms remain unclear.

Methods: We began by identifying Niemann-Pick C1 (NPC1) as a key cholesterol uptake gene linked to cancer progression through clinical data analysis. Using three tumor models, we showed that NPC1 promotes tumor growth by suppressing pyroptosis. Finally, we demonstrated that the NPC1 inhibitor U18666A effectively inhibits tumor growth, supporting its therapeutic potential.

Results: Here we report that NPC1, a key player in cholesterol transport, protects cancer cells from pyroptosis across multiple cancer types. NPC1 expression was highly elevated in human cancers and negatively correlated with patient survival. NPC1 deficiency led to reduced cancer growth and enhanced sensitivity to pyroptosis under pyroptotic stress. NPC1 protects cancer cells from pyroptosis by maintaining cholesterol homeostasis and facilitating LDL-mediated cholesterol uptake, leading to enhanced geranylgeranyl pyrophosphate synthesis for cancer cell survival. Moreover, NPC1 inhibitor U18666A induced cancer cell pyroptosis and was highly therapeutic, either alone or combined with chemotherapeutics, against human hematologic and solid cancers in xenograft mouse models.

Conclusion: This study reveals that NPC1 may be a potential therapeutic target for the treatment of human cancers.

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NPC1作为癌症诱导焦亡的新治疗靶点。

背景：胆固醇代谢重编程是癌细胞通过吸收低密度脂蛋白（LDL）产生用于生长的胆固醇而表现出胆固醇成瘾的一个标志。然而，其潜在机制仍不清楚。方法：我们首先通过临床数据分析确定Niemann-Pick C1 （NPC1）是与癌症进展相关的关键胆固醇摄取基因。通过三种肿瘤模型，我们发现NPC1通过抑制焦亡来促进肿瘤生长。最后，我们证明了NPC1抑制剂U18666A有效抑制肿瘤生长，支持其治疗潜力。结果：在这里，我们报道了NPC1，胆固醇转运的关键参与者，保护多种癌症类型的癌细胞免于焦亡。NPC1在人类癌症中的表达高度升高，并与患者生存率呈负相关。NPC1缺乏导致肿瘤生长减少，并在焦亡应激下增强对焦亡的敏感性。NPC1通过维持胆固醇稳态和促进ldl介导的胆固醇摄取来保护癌细胞免于焦亡，从而增强香叶香叶基焦磷酸合成，促进癌细胞存活。此外，在异种移植小鼠模型中，NPC1抑制剂U18666A诱导癌细胞焦亡，并且单独或联合化疗药物对人类血液学和实体癌具有很高的治疗作用。结论：本研究揭示了NPC1可能是治疗人类癌症的潜在靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biomarker Research Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

15.80

自引率

1.80%

发文量

审稿时长

10 weeks

期刊介绍： Biomarker Research, an open-access, peer-reviewed journal, covers all aspects of biomarker investigation. It seeks to publish original discoveries, novel concepts, commentaries, and reviews across various biomedical disciplines. The field of biomarker research has progressed significantly with the rise of personalized medicine and individual health. Biomarkers play a crucial role in drug discovery and development, as well as in disease diagnosis, treatment, prognosis, and prevention, particularly in the genome era.