HSP90 inhibition attenuated isoflurane-induced neurotoxicity in mouse and human neuroglioma cells

Isoflurane is one of the most popular inhalation anesthetics in the clinical practice but presenting an increased risk of neuronal injury. Hsp90 has been indicated to present an important role for maintaining neuronal homeostasis under the stress. However, the effect of hsp90 during isoflurane exposure is poorly understood. Here in this study, we aimed to observe the protect effect of hsp90 inhibition, and investigate the potential regulatory mechanism after isoflurane exposure. We found that hsp90 inhibitor, 17AAG, showed a great protective effect in maintaining isoflurane-induced ferroptosis of mice hippocampus and cultured neuronal cells. We focus on the crucial protein GPX4 activity in ferroptosis, and found that the 17 AAG contributed its protect effect to preserve physiological level of GPX4 activity under isoflurane exposure, although 17AAG could restored the protein level of GPX4. Further, we observed CMA pathway was activated and then mediated GPX4 degradation under isoflurane exposure. And 17AAG could interfere the complex between hsp90 and lamp2a to inhibit CMA activity, followed by blocking GPX4 degradation, which further affected the isoflurane-induced ferroptosis. Based on these findings, we proposed that hsp90 inhibition as a protective mechanism against isoflurane-induced ferroptosis in neurons.