β-sitosterol suppresses malignant biological behaviors and glycolysis via modulating YBX1-hnRNP K interaction in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung malignancy. As a type of phytosterol, β-sitosterol shares structural similarities with cholesterol and has been shown to possess multiple pharmacological properties. This study aimed to investigate how β-sitosterol influences the progression of NSCLC. To assess the impact of β-sitosterol on NSCLC cells, a treatment with a range of concentrations was administered. Subsequent analyses included cell viability (CCK-8 assay), proliferation (EdU incorporation), migration and invasion (Transwell chambers), apoptosis (flow cytometry), and glycolytic metabolism. Interactions between Y-box binding protein 1 (YBX1) and heterogeneous nuclear ribonucleoprotein K (hnRNP K) were predicted using STRING, DMFold, and molecular docking approaches, with subsequent validation by co-immunoprecipitation. To verify their functional roles, genetic modification techniques including overexpression and knockdown were employed. β-sitosterol dose-dependently inhibited malignant biological behaviors and glycolysis while promoting apoptosis. Notably, β-sitosterol suppressed YBX1-hnRNP K binding without altering their expression. Moreover, YBX1 overexpression or YBX1 mutation promoted malignancy and glycolysis, whereas hnRNP K silencing reversed these effects. In this in vitro study, β-sitosterol suppressed malignant biological behaviors and glycolysis. This effect was associated with suppressed YBX1-hnRNP K interaction in NSCLC cells. Although the precise mechanism by which β-sitosterol disrupts this interaction remains to be elucidated, our findings identify the YBX1–hnRNP K complex as a potential mediator of β-sitosterol’s anti-tumor activity in NSCLC.