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
  • 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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