Novel mechanism of hypidone hydrochloride (YL-0919) in Parkinson's disease: inhibiting neuronal ferroptosis by targeting the Sigma1R-PI3K-AKT-ACSL4 axis.

Increasing evidence suggests antidepressants possess neuroprotective and anti-inflammatory properties. Hypidone hydrochloride (YL-0919), a novel antidepressant with rapid antidepressant effects currently in Phase II clinical trials, exhibits antidepressant, anxiolytic, and cognitive-enhancing activities, but its potential role in Parkinson's disease (PD)-related neuronal damage remains unexplored. Here, we investigated the effects of YL-0919 on an MPTP-induced PD mouse model and on MPP+-induced neuronal damage model. This study demonstrated that YL-0919 ameliorated PD pathology in mice, as evidenced by reduced symptom severity, attenuated inflammatory response, diminished neuronal damage, and improved motor dysfunction. Furthermore, YL-0919 reduced ferroptosis in MPP+-induced SH-SY5Y and PC12 cells by reduced Fe2+ staining, intracellular ROS, lipid peroxidation levels, and mitochondrial membrane potential. Mechanistically, YL-0919 inhibited neuronal ferroptosis by regulating the Sigma1R-PI3K-AKT-ACSL4 axis, thereby alleviating neurological impairment. These findings reveal a novel neuroprotective mechanism of YL-0919 in PD, highlighting the Sigma1R-PI3K-AKT-ACSL4 axis as a promising therapeutic target for mitigating PD symptoms through ferroptosis inhibition.