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

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

  • Neuropharmacology. 2026 Jul 1:292:110950. doi: 10.1016/j.neuropharm.2026.110950.
Mengying Huang 1,  Yanmin Lyu 2,  Jixiang Sun 3,  Chunxiao Du 2,  Junrui Chen 2,  Jiawen Lu 4,  Ge Li 2,  Zhiding Wang 2,  Jun Zhang 5,  Yunfeng Li 6,  Yuxiang Li 7,  Gencheng Han 8
Affiliations

Affiliations

  • 1 Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cell and Molecular Immunology, School of Medical Sciences, Henan University, Kaifeng, 475000, China; Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
  • 2 Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
  • 3 School of Basic Medical Sciences, Anhui Medical University, Hefei, 230031, China.
  • 4 Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cell and Molecular Immunology, School of Medical Sciences, Henan University, Kaifeng, 475000, China.
  • 5 Joint National Laboratory for Antibody Drug Engineering, Key Laboratory of Cell and Molecular Immunology, School of Medical Sciences, Henan University, Kaifeng, 475000, China. Electronic address: [email protected].
  • 6 Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. Electronic address: [email protected].
  • 7 Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. Electronic address: [email protected].
  • 8 Beijing Institute of Basic Medical Sciences, Beijing, 100850, China. Electronic address: [email protected].
PMID: 41887568 DOI: 10.1016/j.neuropharm.2026.110950
Abstract

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.

Keywords

ACSL4; AKT; PI3K; Parkinson's disease; Sigma1R; YL-0919.

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