Mitophagy-mediated ferroptosis involved in 2,5-hexanedione-induced neurotoxicity in rats
摘要
n-Hexane,a widespread environmental and industrial pollutant,poses serious health risks,particularly neurotox-icity.Chronic exposure primarily induces sensorimotor neuropathy via its metabolite 2,5-hexanedione(HD),yet the mechanisms underlying HD-induced neuronal injury remain unclear.Recent evidence implicates ferroptosis,an iron-dependent form of regulated cell death,in neurodegenerative processes.In this study,Sprague-Dawley(SD)rats were exposed to HD to establish a neuropathy model.Ferroptosis involvement was assessed using the iron chelator deferoxamine(DFO)and the ferroptosis inhibitor Ferrostatin-1.The potential role of mitophagy in HD-induced ferroptosis was evaluated by monitoring mitophagy markers and by autophagy inhibition with chloroquine(CQ).In vitro,SH-SY5Y cells were transfected with PINK-1 siRNA to explore mitophagy-mediated regulation of ferroptosis.HD exposure led to iron accumulation,lipid peroxidation,mitochondrial abnormalities,and decreased GPX4 in rat spinal neurons.DFO or ferrostatin-1 treatment ameliorated these changes and pre-served mitochondrial integrity.Mechanistic analyses revealed HD-induced activation of mitophagy,as shown by upregulation of Beclin-1,LC3II,Drp-1,and PINK-1,with concomitant downregulation of P62 in spinal mitochon-dria.CQ suppressed mitophagy,reduced iron deposition and lipid peroxidation,and improved motor function.Similarly,PINK-1 knockdown in SH-SY5Y cells mitigated HD-induced mitophagy and ferroptosis.These find-ings demonstrate that HD induces neuronal ferroptosis via mitophagy activation.Inhibition of ferroptosis or mitophagy effectively attenuates HD-induced neurotoxicity,suggesting potential therapeutic strategies to reduce neural damage from environmental n-hexane exposure.
