Fangchinoline suppresses nasopharyngeal carcinoma progression by inhibiting SQLE to regulate the PI3K/AKT pathway dysregulation

Background and Purpose: Squalene epoxidase (SQLE), a key enzyme in cholesterol metabolism, remains underexplored in nasopharyngeal carcinoma (NPC). Additionally, the therapeutic potential of Fangchinoline, an alkaloid with anticancer properties, has yet to be systematically evaluated. This research investigates Fangchinoline's efficacy in NPC treatment and SQLE-related mechanisms. Methods: Drug screening in NPC cell lines C666-1 and 5-8F identified potential candidates. IC50 values were determined using CCK-8 assays, and apoptosis, proliferation, and invasion were assessed via Annexin V/PI staining, EdU staining, and Transwell assays. Cholesterol levels were quantified using a TG kit. RNA sequencing with GO/KEGG analyses identified key pathways. Correlation analysis was performed via cBioPortal and GEPIA2 databases, protein interaction networks via STRING and Cytoscape, and survival analysis via Kaplan-Meier curves. Gene and protein expression were validated with qPCR and Western blot, and an NPC mouse model confirmed in vivo efficacy. Results: Fangchinoline inhibited NPC cell proliferation, induced apoptosis, and reduced cholesterol accumulation. RNA sequencing revealed that Fangchinoline downregulated SQLE expression, suppressing the PI3K/AKT pathway. Correlation and protein interaction analyses highlighted SQLE's role in NPC progression, and survival analysis confirmed its clinical relevance. By targeting SQLE and disrupting cholesterol metabolism, Fangchinoline suppressed tumor growth both in vitro and in vivo. Conclusion: Our study demonstrates that Fangchinoline inhibits NPC growth by targeting SQLE and disrupting the PI3K/AKT pathway, providing new insights into SQLE as a therapeutic target in NPC.