Targeting promoter G-quadruplex of SIRT3 with valsartan and candesartan as a therapeutic strategy to downregulate its expression in lung cancer.

Sirtuin 3 (SIRT3), an NAD+-dependent histone deacetylase, plays dual roles in cancer by regulating metabolism, oxidative stress, and chemoresistance. Emerging evidence implicates noncanonical DNA secondary structures called G-quadruplexes (GQs) in gene regulation. We identified and characterized a stable hybrid GQ motif in the SIRT3 promoter, located 17 base pairs upstream of the transcription start site. This GQ functions as a molecular switch modulating SIRT3 transcription. Stabilization of this promoter GQ by the canonical ligand BRACO-19 markedly reduced SIRT3 levels in lung cancer cells, and two clinically approved angiotensin II receptor blockers, candesartan and valsartan, also suppressed cell viability by selectively targeting this GQ motif. Our findings reveal a novel epigenetic mechanism for SIRT3 transcriptional control and highlight promoter-GQ structures as actionable therapeutic targets, supporting both rational ligand design and drug repurposing strategies for cancer therapy.