Promoting KAT5-Mediated CUL5 Lactylation to Downregulate MAVS/NLRP3 Signaling in the Hippocampus: The Novel Mechanisms Underlying Hydrogen Sulfide-Ameliorated Cognitive Dysfunction in Parkinson's Disease.

Cognitive dysfunction is a prevalent non-motor manifestation of Parkinson's disease (PD). Our previous work demonstrated that hydrogen sulfide (H2S) holds promise for preventing and treating cognitive deficits in PD, an effect closely associated with promoting hippocampal lactate production. However, the underlying molecular mechanisms remain incompletely understood. Here, we show that NaHS, an exogenous H2S donor, enhanced lysine acetyltransferase 5 (KAT5)-mediated Cullin 5 (CUL5) lactylation, promoted the interaction between CUL5 and mitochondrial antiviral signaling protein (MAVS), and suppressed MAVS/NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) signaling in the hippocampus of PD rats with cognitive dysfunction. These effects were abolished by hippocampal injection of AAV-K85R-CUL5 (which blocks CUL5 lactylation) or AAV-KAT5-shRNA (which knocks down KAT5). Moreover, inhibition of CUL5 lactylation reversed the beneficial effects of H2S on cognitive dysfunction. Consistently, overexpression of MAVS via AAV-MAVS injection into the hippocampus also abrogated the H2S-mediated cognitive improvement. Overall, these results revealed that promoting KAT5-mediated CUL5 lysine lactylation to inhibit MAVS/NLRP3 signaling contributes to H2S-induced improvement in cognitive dysfunction in PD rats, thereby providing a solid theoretical foundation for therapeutic strategies targeting H2S to mitigate cognitive impairment in PD.