Multienzyme-like Reactivity Cooperatively Impairs Glutathione Peroxidase 4 and Ferroptosis Suppressor Protein 1 Pathways in Triple-Negative Breast Cancer for Sensitized Ferroptosis Therapy

Abstract

Ferroptosis is a recently discovered route of regulated cell death that offers the opportunities for the treatment of chemotherapy-resistant tumor indications, but its efficacy can be affected by the glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) antioxidant mechanisms, posing significant challenges for its clinical translation. In this study, we report a Cu-tetra­(4-carboxyphenyl)­porphyrin chloride­(Fe­(III)) (Cu-TCPP­(Fe)) metal organic framework (MOF)-based nanosystem for the efficient incorporation of Au nanoparticles (NPs) and RSL3, which can demonstrate enzyme-like activities to universally suppress the antiferroptotic pathways in tumor cells for amplifying ferroptotic damage. Herein, Cu-TCPP­(Fe) MOF nanosheets were integrated with Au NPs via in situ nucleation and loaded with RSL3 via π–π stacking, which were eventually modified with polyethylene glycol (PEG) and iRGD for tumor-targeted drug delivery. Specifically, the Au NPs can demonstrate glucose oxidase-like activities for efficient glucose depletion, thus disrupting the pentose phosphate pathway to impede reduced glutathione (GSH) biosynthesis and prevent the recycling of coenzyme Q10 (CoQ10) to CoQ10H2, while Cu species can oxidize GSH into oxidized glutathione (GSSG). These nanocatalytic activities can lead to the simultaneous inhibition of the GPX4/GSH and FSP1/CoQ10H2 pathways and cooperate with the GPX4-deactivating function of RSL3 to cause pronounced ferroptotic damage, thereby providing a strong rationale for the application of ferroptosis therapy in the clinic.

Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells

“…Multiple lines of evidence have suggested ferroptosis’ pivotal role in tumor suppressor pathways, including p53 activation, highlighting its relevance in the field of antineoplastic therapies [ 5 , 6 ]. Indeed, several studies have demonstrated the high potential of ferroptosis as a novel therapeutic strategy for the treatment of different cancers, including hepatic, lung and breast cancer [ 7 , 8 , 9 , 10 , 11 , 12 ]. Recent studies have confirmed that female breast cancer (BC) has overtaken lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), closely followed by lung (11.4%), colorectal (10.0%), prostate (7.3%) and stomach (5.6%) cancers.…”

Nanodrugs alleviate acute kidney injury: Manipulate RONS at kidney

“…Coenzyme Q10 (CoQ10), an important electron carrier in the mitochondrial electronic respiratory chain, is an effective RONS scavenger [ 239 ]. However, CoQ10 is hydrophobic and cannot be directly used in AKI treatment.…”

Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

“…Mimetic drugs composed of small-molecule inducers of ferroptosis, erastin, and RSL3 with BH3 were effective in synergistically killing U251 cells and inhibiting malignant progression of glioblastoma ( 111 ). Nanocatalytic activity leads to simultaneous inhibition of GPX4/GSH and FSP1/coq10h2 pathways and synergizes with the GPX4 inactivation function of RSL3 to cause significant ferroptosis damage and thus inhibit malignant progression of triple-negative breast cancer ( 112 ). Depletion of PSTK leads to inactivation of GSH peroxide 4 (GPX4) and inhibition of selenocysteine and cysteine synthesis.…”