Objective To investigate the mechanism by which tetrandrine regulates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) signaling pathway to induce ferroptosis in breast cancer cells based on peroxiredoxin 1 (PRDX1). Methods Human breast cancer MCF-7 cells transfected with PRDX1 siRNA were treated with tetrandrine to examine its effects on cell proliferation, apoptosis, migration and invasion. The levels of malondialdehyde (MDA), Fe²⁺, intracellular and mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, and mitochondrial membrane permeability were measured. Western blotting and qRT-PCR were used to detect the expressions of voltage-dependent anion channel 1 (VDAC1), p53, PI3K/Akt/GSK-3β signaling pathway and nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway related proteins and genes. Results Tetrandrine dose-dependently inhibited MCF-7 cell proliferation, migration and invasion while inducing apoptosis (P < 0.01), increased intracellular and mitochondrial ROS, MDA and Fe²⁺ levels (P < 0.01), aggravated lipid peroxidation, reduced mitochondrial membrane potential (P < 0.01), enhanced mitochondrial membrane permeability (P < 0.01), upregulated HO-1, p53, GSK-3β and VDAC1 expressions (P < 0.01), downregulated Nrf2, PI3K, p-PI3K, Akt and p-Akt expressions (P < 0.01). Knockdown of PRDX1 gene significantly amplified these effects of tetrandrine (P < 0.01). Conclusion Tetrandrine induces mitochondria-associated ferroptosis in MCF-7 cells via PI3K/Akt/GSK-3β signaling pathway, with PRDX1 playing a critical regulatory role.

tetrandrine  /  PRDX1  /  breast cancer  /  ferroptosis  /  PI3K/Akt/GSK-3β signaling pathway