Hydrogen sulfide protects against spinal cord pyroptosis via persulfidation of Rac1 after lumbosacral plexus nerve injury.

Pyroptosis, a form of lytic and inflammatory programmed cell death mediated by gasdermin proteins, contributes to progressive spinal cord neurodegeneration following neural trauma. Nevertheless, the regulatory mechanisms governing this process remain inadequately characterized. In this investigation, hydrogen sulfide (H₂S) was identified as an endogenous inhibitor of neuronal pyroptosis, functioning through Rac1-dependent NLRP3 inflammasome signaling. In a rat model of lumbosacral plexus nerve injury, H₂S treatment significantly decreased pyroptosis-associated markers (NLRP3, caspase-1, GSDMD) and enhanced neuronal survival. In vitro, the administration of H₂S effectively mitigated hypoxia-induced neuronal pyroptosis by inhibiting the assembly of the NLRP3 inflammasome. Mechanistically, our findings indicate that H₂S selectively persulfidates Rac1, inhibiting its GTPase activity and reducing reactive oxygen species (ROS) production, both of which are critical for inflammasome priming. Molecular dynamics simulations and site-directed mutagenesis further confirmed that H₂S persulfidation of Rac1 at Cys178 alters its conformation, thereby suppressing NLRP3 inflammasome activation. Taken together, our findings reveal a novel post-translational regulatory mechanism by which H₂S mitigates pyroptotic neuronal death through Rac1 persulfidation, highlighting the H₂S-Rac1 axis as a promising therapeutic target for neuroprotection in pyroptosis-related neurodegeneration.