Ferroptosis offers a promising therapeutic vulnerability in triple-negative breast cancer (TNBC), yet resistance limits efficacy in the predominant basal-like subtype. Here, we demonstrate that peroxiredoxin 4 (PRDX4) is a key regulator of this ferroptosis resistance. Functionally, PRDX4 suppresses ferroptosis by inhibiting lipid peroxidation in the endoplasmic reticulum (ER) and reducing the formation of mitochondria-associated membranes (MAMs), thereby blocking interorganellar lipid and calcium transfer. Mechanistically, PRDX4 dimers competitively bind the substrate-binding domain of GRP75, impeding the assembly of the IP3R3-GRP75-VDAC1 complex. Notably, this inhibitory function relies on protein-protein interactions rather than its conserved peroxidase activity. Therapeutically, targeted PRDX4 degradation via the E3 ubiquitin ligase ARIH1 or the small molecule compound TLC69 effectively induces ferroptosis and suppresses tumor growth in vivo. Collectively, our study reveals the role of PRDX4 as a ferroptosis suppressor, delineates a PRDX4-GRP75-MAMs regulatory axis, and provides a potential targeting strategy to sensitize TNBC to ferroptosis.