Work

Sanguinarine alleviates cisplatin-induced apoptosis in AKI by upregulating BCL-2 through targeting the gene promoter i-motif

Year: 2025

Type: article

Abstract: Acute kidney injury (AKI) is a severe clinical condition with high morbidity and mortality. Apoptosis of renal tubular epithelial cells is a key pathological driver, and upregulation of the anti-apoptotic protein BCL-2 is a validated protective mechanism. The BCL-2 promoter harbors a C-rich sequence capable of forming an i-motif, a non-canonical DNA secondary structure with regulatory functions. Previous studies have reported steroid-like molecules as potential ligands for the BCL-2 i-motif, but their interactions were generally weak and lacked systematic pharmacophore insight. Here, we identify Sanguinarine ( SG ), a benzophenanthridine alkaloid, as a more potent ligand from a natural product library. Surface plasmon resonance (SPR) revealed broad-spectrum binding of SG to multiple promoter i-motifs, yet circular dichroism (CD) and melting assays suggested a relatively stronger stabilizing effect on the BCL-2 C-rich structure under our assay conditions. This apparent conformational preference, rather than strict binding selectivity, led to transcriptional activation of BCL-2 and protection of HK-2 cells from cisplatin-induced apoptosis. While i-motifs have only rarely been explored in AKI, our study provides new mechanistic insight by defining an aromatic–cationic pharmacophore and suggesting that structure-dependent stabilization may serve as a plausible mechanism for promoter-specific modulation. These findings support the biological relevance of the BCL-2 i-motif and highlight natural products as valuable scaffolds for nucleic-acid–interacting agents in renal injury models.

Source: European Journal of Medicinal Chemistry Reports

DOI: 10.1016/j.ejmcr.2025.100316