Aims: Cystathionine β-synthase (CBS) is essential for homocysteine (Hcy) transsulfuration, yielding cysteine as a common precursor of hydrogen sulfide (H₂S), glutathione (GSH), and other sulfur molecules, which produce neuroprotective effects in neurological conditions. We previously reported a disruption of microglial CBS/H₂S signaling in a Parkinson's disease (PD) mouse model. Yet, it remains unclear whether CBS affects nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome activity and other pathologies in PD. Results: Microglial CBS expression decreased after lipopolysaccharide (LPS) stimulation. Elevated GSSG (the oxidized GSH) content and decreased H₂S generation were found in the brains of microglial cbs conditional-knockout (cbs^cKO) mice, whereas serum and brain Hcy levels remained unaltered. Moreover, microglial cbs^cKO mice were susceptible to NLRP3 inflammasome activation and dopaminergic neuron losses caused by LPS injection into the substantia nigra, whereas cbs overexpression or activation produced opposite effects. In vitro studies showed that cbs overexpression or activation suppressed microglial NLRP3 inflammasome activation and interleukin (IL)-1β secretion by reducing mitochondrial reactive oxygen species (mitoROS) level. Conversely, ablation of cbs enhanced NLRP3 expression and mitoROS generation and augmented microglial NLRP3 inflammasome activity in response to adenosine triphosphate challenge, which was blocked by the mitoROS scavenger. Innovation and Conclusion: The study demonstrated an elevated GSSG level and reduced H₂S generation, which correlated with a susceptible status of microglia in the brain of cbs^cKO mice. Our findings reveal a critical role of CBS in restraining the microglial NLRP3 inflammasome by controlling redox homeostasis and highlight that activation or upregulation of CBS may become a potential strategy for PD treatment.

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