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

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.