Zinc Protoporphyrin Functions as a Ferroptosis Inducer to Activate Heme-BACH Axis and Potently Suppress IDH1-Mutant...

Ferroptosis shows promise as a cancer treatment due to lipid hydroperoxide accumulation in an iron-dependent manner. Isocitrate dehydrogenase 1 (IDH1) mutation is common in gliomas and D-2-hydroxyglutarate (D-2HG) sensitizes cancer cells to ferroptosis. However, the regulation of ferroptosis in IDH1 mutant gliomas remains unclear. We hypothesize that IDH1 mutations induce glioma ferroptosis by regulating iron metabolism and antioxidant systems through the heme-BACH axis.

IDH1 mutation induces ferroptosis in astrocytes and glioma cells demonstrated by growth inhibition, mitochondrial damage, and lipid peroxidation. In IDH1-mutant gliomas, both Fe²⁺ and reactive oxygen species accumulate due to impaired heme biosynthesis and thus BACH activation-dependent transcriptional repression of iron homeostasis and antioxidant response-related genes. The heme analogs zinc and tin protoporphyrin IX (ZnPP and SnPP) function as competitive inhibitors to reduce heme-dependent degradation of BACH and to exacerbate ferroptosis, especially for IDH1 mutants at extremely low concentrations. Primary mouse astrocytes and human glioma cell lines were used to determine the effect of IDH1 mutation on ferroptosis, while orthotopic xenograft models were used to evaluate heme analog efficacy. The drug affinity responsive target stability assay was used to determine the interaction between heme and its analog and BACH.

We discover that IDH1 mutation induces ferroptosis by activating the heme-BACH axis. ZnPP, previously believed to function exclusively as a heme oxygenase-1 inhibitor, can competitively bind to BACH to exacerbate ferroptosis and potently suppress IDH1-mutant gliomas. This study reveals a novel metabolic mechanism for inducing ferroptosis and provides a potential therapeutic target for IDH-mutant gliomas. Paraffin-embedded human glioma samples were collected from Xijing Hospital, the First Affiliated Hospital of the Fourth Military Medical University (China) (project number: KY20233192-1). Antioxid. Redox Signal. 44, 145-163.