A pretest on cuproptosis: Activating PPARγ inhibits cuproptosis following intracerebral hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is a severe stroke subtype with high mortality and disability. Cuproptosis is a regulatory cell death modality dependent on intracellular copper ion concentration, the role of which in ICH is unclear. Upon activation by ligand agonists, peroxisome proliferator-activated receptor-γ (PPARγ), can alleviate brain injury after ICH. To investigate the inhibitory effect of activating PPARγ on cuproptosis following ICH, we established the ICH model in vivo and in vitro and they were treated with the PPARγ agonist or antagonist after models being established successfully. Then, the copper ion concentration was measured by copper colorimetric assay and the expression of cuproptosis-related regulatory factors and copper transporter 1 was detected by western blotting and immunofluorescence staining (except in the cell level). We found that the increase in copper ion concentration following ICH leads to the disruption of copper homeostasis, inducing cuproptosis via copper toxicity. Activating PPARγ regulates the expression of cuproptosis-associated positive or negative regulatory factors and mitigates copper toxicity by inhibiting the influx of copper ions into the cell, thereby inhibiting cuproptosis. This study not only reveals the relationship between ICH and cuproptosis but also may provide new therapeutic strategies for improving the prognosis of patients with ICH.