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 4T1 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.