2. Academic Validation
  3. Sino-C, a novel sinomenine derivative, induces cell death by disrupting cholesterol homeostasis in colorectal cancer cells

Sino-C, a novel sinomenine derivative, induces cell death by disrupting cholesterol homeostasis in colorectal cancer cells

  • Acta Pharmacol Sin. 2025 Nov 3. doi: 10.1038/s41401-025-01683-8.
Yan-Ming Zhang 1,  Hui Lu 2,  Bing-Jie Xiao 1,  Chun-Cao Xu 2,  Fan-Fan Zhou 3,  Ting Li 4 5,  Zha-Jun Zhan 6,  Jin-Jian Lu 7 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 99078, China.
  • 2 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 300014, China.
  • 3 Molecular Drug Development Group, Sydney Pharmacy School, The University of Sydney, Camperdown, NSW, 2050, Australia.
  • 4 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 99078, China. [email protected].
  • 5 MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao SAR, 99078, China. [email protected].
  • 6 College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 300014, China. [email protected].
  • 7 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, 99078, China. [email protected].
  • 8 MoE Frontiers Science Center for Precision Oncology, University of Macau, Macao SAR, 99078, China. [email protected].
  • 9 Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Macao SAR, 99078, China. [email protected].
PMID: 41184618 DOI: 10.1038/s41401-025-01683-8
Abstract

Colorectal Cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, necessitating the discovery of novel therapeutic agents. Sinomenine (Sin), a natural product derived from traditional Chinese medicine, has been extensively modified to enhance its therapeutic potential. Here, we synthesized Sino-C, a novel Sin derivative, and evaluated its anti-CRC activity. Sino-C exhibited significant Anticancer effects both in vitro and in vivo. Mechanistically, Sino-C upregulated Cholesterol homeostasis-related genes and increased intracellular Cholesterol levels in CRC cells. Cholesterol depletion with methyl-β-cyclodextrin (MβCD) alleviated Sino-C-induced Cholesterol accumulation, reduced cell death, and reversed cleaved PARP expression, indicating Cholesterol imbalance as a critical mediator of Sino-C's activity. Furthermore, Sino-C-induced Cholesterol imbalance promoted lipid peroxidation and endoplasmic reticulum (ER) stress, contributing to cell death. The antioxidant vitamin E (Ve), N-acetylcysteine (NAC), or PERK Inhibitor GSK2656157 could reverse these effects of Sino-C. Clinical correlation analysis further revealed that high expression of Sino-C-upregulated Cholesterol homeostasis genes was linked to better survival outcomes in CRC cohorts. In conclusion, this study highlights the therapeutic potential of Sino-C in CRC. In vitro mechanistic findings suggest that Sino-C exerts its Anticancer effects through modulation of Cholesterol metabolism, positioning natural product derivatives as valuable candidates for further development.

Keywords

ER stress; cholesterol; colorectal cancer; lipid peroxidation; sinomenine derivative.

Figures
Products