This paper relates the effect of ATH434 because, in the first PBT434 paper ( Finkelstein et al 2017), it was found that PBT434 increases DJ-1. Now this paper deals with brain ischemia-reperfusion injury, a very big potential indication for ATH434. It looks like ATH434 will be able to inhibit ferroptosis in these common vascular problems. Of course, a study to confirm this is needed.

Neurochem Int

. 2023 Oct 10:171:105628.

doi: 10.1016/j.neuint.2023.105628. Online ahead of print.

DJ-1 inhibits ferroptosis in cerebral ischemia-reperfusion via ATF4/HSPA5 pathway

Yumei Li ¹, Tianyi Chen ², Ying Xue ², Yuan Wang ², Li Peng ², Chenglong Wang ³, Shanshan Yu ⁴

Affiliations expand

• PMID: 37820776

DOI: 10.1016/j.neuint.2023.105628

Abstract

DJ-1 has been confirmed to have neuroprotective effects. Ferroptosis is an iron-dependent programmed cell death mode associated with ischemic stroke. The ATF4/HSPA5 pathway has been shown to play an important role in the regulation of ferroptosis. To explore the role and possible mechanism of DJ-1 in regulating ferroptosis in cerebral ischemia-reperfusion injury. In this study, Middle cerebral artery occlusion/reperfusion (MCAO/R) was used to simulate cerebral ischemia-reperfusion injury in vivo. Detected ferroptosis-related indicators and observed mitochondrial morphology in brain tissue using transmission electron microscopy. ATF4 was subsequently interfered to observe the effect of DJ-1 on ferroptosis. The results suggest that after interfering with DJ-1, the iron content and malondialdehyde (MDA) content of ferroptosis-related indicators increased, the GSH content decreased, and the mitochondrial structure was severely damaged. We then found that DJ-1 attenuated ferroptosis following ATF4 reduction. In this study, we found that the neuroprotective effect of DJ-1 is related to the inhibition of ferroptosis, and its molecular mechanism is closely related to the ATF4/HSPA5 pathway, which may play a key role in inhibiting brain ischemia-reperfusion (I/R) ferroptosis.

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