Tetrahydroberberine targets the bcl-2 promoter G-quadruplex to trigger mitochondrial apoptosis and inhibit nasopharyngeal carcinoma progression.

Tetrahydroberberine (THB), a reduced derivative of berberine, exhibits favorable pharmacological properties, including cardiovascular benefits and neuroprotective effects. However, its antitumor activity and underlying molecular mechanisms remain largely unexplored. B-cell lymphoma 2 (bcl-2), a key anti-apoptotic gene, is frequently overexpressed in various cancers, including nasopharyngeal carcinoma (NPC). In this study, we investigated the anti-NPC effects of THB and elucidated its antitumor mechanism through targeting bcl-2. Biophysical analyses demonstrated that THB specifically binds to and stabilizes the G-quadruplex (G4) structure within the bcl-2 promoter with high affinity. Both in vitro and in vivo assays revealed that THB markedly inhibited NPC cell proliferation in a dose-dependent manner. Notably, THB treatment activated the mitochondrial apoptotic pathway, as evidenced by the upregulation of the pro-apoptotic protein Bax and cleaved caspase-3, accompanied by the downregulation of the anti-apoptotic protein bcl-2. Collectively, these findings indicate that THB induces apoptosis in NPC cells by targeting and stabilizing the bcl-2 G4 structure and modulating the Bax/bcl-2/caspase-3 signaling axis. This study highlights THB as a promising G4-stabilizing agent for cancer therapy and provides a theoretical foundation for the rational design of next-generation G4-targeted anticancer lead compounds.