ΔA146Ply exerts anti-triple-negative breast cancer effects by inducing ferroptosis via regulation of the CYP24A1-mediated calcitriol-vitamin D receptor pathway.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, typically associated with poor clinical outcomes. Recently, ferroptosis has emerged as a promising therapeutic target for TNBC. ΔA146Ply, a novel pneumolysin variant, has demonstrated potential as an anti-tumor agent; however, its role in regulating ferroptosis remains unclear. This study investigates whether ΔA146Ply exerts anti-TNBC effects by promoting ferroptosis via the CYP24A1-mediated Calcitriol/vitamin D receptor (VDR) pathway. Our in vitro results reveal that ΔA146Ply inhibits MDA-MB-231 cells by inducing ferroptosis. Mechanistically, we demonstrate that CYP24A1 negatively regulates the Calcitriol-VDR pathway and serves as a critical mediator of ferroptosis. In vivo, ΔA146Ply suppresses TNBC tumor growth by downregulating CYP24A1 and promoting ferroptosis. In conclusion, ΔA146Ply exerts anti-TNBC effects by activating ferroptosis through the regulation of the CYP24A1-mediated Calcitriol-VDR pathway.