Curcumin prevents neurodegeneration by blocking HDAC6-NLRP3 pathway-dependent neuroinflammation in Parkinson's disease.

Curcumin is a hydrophobic polyphenolic compound with potent anti-inflammatory properties. However, whether it can achieve therapeutic effects by alleviating neuroinflammation in patients with Parkinson's disease (PD) and its potential mechanism are still unknown. This study explored the effects of curcumin on neuroinflammation in dopaminergic neurons and deciphered its direct target in the histone deacetylase 6 (HDAC6)-Nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) pathway, revealing the potential role of curcumin in the treatment of Parkinson's disease. Here, we show that curcumin alleviated the degeneration of neurons in a PD model by mitigating the activation of the NLRP3-mediated inflammatory response both in vivo and in vitro. Furthermore, we discovered that curcumin prevented neuroinflammation by blocking the HDAC6-NLRP3 pathway in a PD model. Moreover, overexpression of HDAC6 could eliminate the effect of curcumin on the neuroinflammatory response mediated by NLRP3. Curcumin and the HDAC6 inhibitor WT161 could alleviate neurodegeneration. In addition, activated HDAC6 directly deacetylated NLRP3 at lysine 84 to maintain its stability, which increased the inflammatory response and promoted neurodegeneration. These findings show that curcumin, a neuroinflammation inhibitor, blocks neurodegeneration via the HDAC6-NLRP3 pathway and represents a potentially practical pharmacological approach for treating neuroinflammation-driven neurodegenerative diseases. For the first time, HDAC6 was shown to directly regulate the acetylation of NLRP3.