Pharmacological inhibition of USP7 attenuates deltamethrin-induced neuronal ferroptosis via GPX4 stabilization

Abstract

Recent studies suggest a significant association between deltamethrin (DM) exposure and an elevated risk of neurodegenerative diseases, yet the underlying molecular mechanisms remain poorly understood. The role of Ubiquitin-specific protease 7 (USP7), a key deubiquitinating enzyme regulating protein homeostasis, in DM-induced neurotoxicity is particularly elusive. Here, we combined in vitro HT22 mouse hippocampal neuronal cells and in vivo male C57BL/6 J mice, which received daily oral gavage of DM at 4.5, 9.0, and 18.0 mg/kg for 30 consecutive days, to investigate the molecular mechanisms underlying DM-induced neurotoxicity. DM exposure significantly induced ferroptosis which was characterized by lipid peroxidation, disruption of iron homeostasis, mitochondrial damage and GPX4 degradation in HT22 cells and in the hippocampus, and was accompanied by impaired spatial learning and memory and neuronal hyperexcitability in mice. Consistently, DM decreased GSH and SOD levels, increased MDA and Fe²⁺, and reduced GPX4, supporting ferroptosis-associated oxidative injury in both models. Mechanistically, DM treatment markedly increased USP7 expression and enhanced GPX4 ubiquitination, thereby promoting its degradation. Increased USP7 levels subsequently induced the ubiquitination of GPX4. Critically, inhibition of USP7 reversed DM-induced GPX4 degradation, lipid peroxidation, iron dysregulation, and mitochondrial damage, thereby stabilizing GPX4 and mitigating neuronal ferroptosis. In conclusion, our findings identify that the upregulation of USP7 is a key mechanism in DM-induced neurotoxicity. USP7 promotes GPX4 degradation via ubiquitination, and inhibition of USP7 preserves GPX4 stability, thereby protecting neurons from ferroptosis and highlighting USP7 as a promising therapeutic target for preventing and treating DM-induced neurotoxicity.