Ruscogenin Suppresses Nasopharyngeal Carcinoma Progression by Downregulating KDM1A to Co-induce Ferroptosis and Apoptosis.

Abstract

Nasopharyngeal carcinoma (NPC) is a highly aggressive malignancy. The natural compound ruscogenin (Rus) shows anti-cancer potential. This study elucidates the specific mechanism of action in nasopharyngeal carcinoma (NPC) by investigating its effects on NPC cells and the underlying molecular pathway. The human nasopharyngeal carcinoma (NPC) cell line, C666-1, was treated with various concentrations of Rus. A series of in vitro assays was performed to evaluate cell viability, proliferation, migration, invasion, apoptosis, and ferroptosis. The role of lysine-specific demethylase 1A (KDM1A) was investigated using Western blot and molecular docking, and its mediating role was validated through overexpression rescue experiments. Ruscogenin dose-dependently diminished the proliferative, clonogenic, migratory, and invasive capacities of C666-1 cells. Mechanistically, Rus treatment induced both apoptosis, evidenced by the activation of executioner caspase-3 and a shift towards pro-apoptotic signaling via the Bax/Bcl-2 balance, and ferroptosis, marked by elevated lipid peroxidation and intracellular iron. These anti-tumor effects were strongly correlated with the downregulation of KDM1A. Crucially, the forced overexpression of KDM1A significantly attenuated Rus-induced apoptosis and ferroptosis, and reversed the suppression of malignant phenotypes, confirming KDM1A's critical mediating role. Ruscogenin inhibits the malignant progression of nasopharyngeal carcinoma by downregulating KDM1A, thereby promoting apoptosis and ferroptosis. These findings identify the Rus-KDM1A axis as a promising therapeutic target for NPC treatment.