The H

Abstract

Hydrogen sulfide (H₂S) plays a crucial neuroprotective role in Parkinson's disease (PD). Cystathionine-β-synthase (CBS), a key enzyme involved in H₂S biosynthesis, exhibits expression deficiencies that are closely linked to PD progression. This suggests that enhancing the CBS-H₂S signaling axis to restore H₂S homeostasis may be a critical approach for preventing and treating PD. In the present study, the H₂S donor sulforaphane (SFN) was investigated to elucidate its neuroprotective mechanisms through activation of the CBS-H₂S axis. siRNA-mediated silencing of Nrf2 and CBS was employed to clarify the role of each in SFN's effects. Our findings demonstrate that SFN promotes CBS expression and H₂S synthesis, activates mitophagy to clear damaged mitochondria, reduces mitochondrial-derived reactive oxygen species (mtROS) levels, and inhibits the activation of NLRP3 inflammasomes and caspase-1. In the MPTP-induced PD mouse model, SFN improved motor performance, increased the survival rate of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra, and restored dopamine metabolism in the striatum, normalizing the DOPAC/DA and 5-HIAA/5-HT ratios. Electron microscopy revealed that SFN facilitated the clearance of damaged mitochondria through autophagosomes and blocked mtROS-mediated NLRP3 inflammasome activation. In the MPP+-induced BV-2 microglial cell model, SFN upregulated CBS expression, enhanced H₂S synthesis, increased the LC3-II/I ratio, and inhibited p62 degradation, thereby promoting the recovery of mitochondrial membrane potential and reducing ROS release. These effects were still observed under Nrf2 silencing conditions, indicating that SFN's neuroprotective effects are mediated through the CBS-H₂S axis independently of Nrf2 signaling. Collectively, these findings indicate that SFN reshapes the CBS-H₂S signaling axis, activates mitochondrial autophagy, and suppresses inflammation, offering novel insights into multi-target therapeutic approaches for PD and underscoring the essential role of H₂S in neuroprotection.

Key Findings

• Sulforaphane (SFN) promotes CBS expression and H₂S synthesis, activating mitophagy to clear damaged mitochondria and reduce mitochondrial-derived reactive oxygen species (mtROS).
• SFN inhibits the activation of NLRP3 inflammasomes and caspase-1, thereby suppressing inflammation.
• In MPTP-induced Parkinson's disease mouse models, SFN improves motor performance, increases survival of dopaminergic neurons, and restores dopamine metabolism.
• SFN's neuroprotective effects via the CBS-H₂S axis occur independently of Nrf2 signaling.

Clinical Significance

Citation

Xie Wenyu, Wu Ke, Zhang Linet al.. The H Bioorganic chemistry. 2026-Jun-15.