SBF-1 suppresses colorectal cancer cell growth via modulating cholesterol metabolic reprogramming.

Colorectal cancer (CRC) is a highly prevalent malignancy globally, ranking among the top three causes of cancer-related deaths, which underscores the urgent need for novel therapeutic approaches. Here, we investigated the antitumor activity and mechanism of SBF-1, a bioactive substance isolated from Ornithogalum caudatum Jacq. SBF-1 significantly inhibited the viability of multiple CRC cell lines by inducing dose-dependent degradation of oxysterol-binding protein (OSBP), leading to reduced intracellular cholesterol levels. Further investigation demonstrated that SBF-1 reprograms cholesterol metabolism by suppressing cholesterol biosynthesis while enhancing efflux and esterification pathways, thereby disrupting cellular cholesterol homeostasis. Comparative transcriptomic analysis of SW480 and SW620 colorectal cancer cells identified NPC2 as a key determinant of SBF-1 sensitivity: low NPC2 expression correlated with greater cholesterol depletion and higher cytotoxicity. Knockdown of NPC2 sensitized resistant cells to SBF-1, whereas NPC2 overexpression conferred resistance. Collectively, our findings reveal that SBF-1 exerts potent cytotoxic effects on colorectal cancer cells through OSBP degradation-mediated cholesterol metabolic reprogramming, with NPC2 serving as a critical modulator of cellular susceptibility. This study provides a solid theoretical foundation for the development of novel precision anticancer therapies targeting cholesterol metabolism.