Dual metabolic reprogramming by metal-polyphenol Nanoplatform enhances Ferroptotic therapy for triple-negative breast Cancer

While ferroptotic therapy has emerged as a promising strategy for triple-negative breast cancer (TNBC), cellular ferroptosis resistance poses a significant challenge. Given the compensatory up-regulation of dihydroorotate dehydrogenase (DHODH) following glutathione peroxidase 4 (GPX4, the primary ferroptosis defender) inhibition, concurrent GPX4/DHODH suppression has been recently revealed essential for ferroptosis sensitization. However, DHODH, as a pivotal nucleotide metabolism enzyme, might exert complex even contradictory effects on tumor ferroptotic therapy, which are poorly understood. This work reveals for the first time that brequinar (BQR, a DHODH inhibitor) exerts dual-edged effects on ferroptotic therapy against 4 T1 cells: besides its well-known disruption of cellular redox balance for ferroptosis sensitization, BQR-intervened pyrimidine metabolism blocks tumor growth, accompanied by up-regulation of lipid droplets (LDs), which paradoxically aggravates ferroptosis resistance. To address this dilemma, we pioneer the combination of DGAT1 inhibition for lipid metabolism remodeling. As a proof-of-concept, we fabricate a BQR/A922500 (a DGAT1 inhibitor) co -encapsulated metal-polyphenol network (named AB@HA-TA/Fe) by one-pot method for robust targeted ferroptotic therapy of TNBC. AB@HA-TA/Fe triggers cellular ferroptosis by boosting iron level and dual DHODH/GPX4 suppression; and the combination of A922500 rescues BQR-induced LD up-regulation, reversing ferroptosis resistance. The biosafety and ferroptotic therapy efficacy of AB@HA-TA/Fe are verified both in vitro and in vivo . This work helps to accelerate DHODH inhibitors' clinical translation by elucidating previously overlooked mechanisms limiting DHODH inhibitors' efficacy and proposing synchronous DGAT1 inhibition as a countermeasure. The fabricated nanoweapon AB@HA-TA/Fe presents a novel dual metabolic intervention paradigm for ferroptosis sensitization, proposing an innovative framework for ferroptosis-integrated combination therapy of TNBC.