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Haloperidol inhibits inflammasome activation via LAMTOR1 and reduces the risk of arthritides

Ambati, V.; Yerramothu, P.; Konduri, R.; Nguyen, J.; Gelfand, B. D.; Werner, B. C.; Taylor, E. W.; Wang, S.-b.

2023-12-08 rheumatology
10.1101/2023.12.06.23299609 medRxiv
Show abstract

Gout is the most prevalent form of inflammatory arthritis in the world. Although multiple treatments exist, many patients are poorly responsive. Here we report, using a health insurance database analysis, that use of the anti-psychotic haloperidol is associated with a reduced risk of incident gout. Haloperidol inhibits ASC speck formation, caspase-1 activation, and release of IL-1{beta} and IL-6, suggesting that it inhibits NLRP3 inflammasome activation and downstream cytokine responses. We also identified LAMTOR1 as a novel binding partner for haloperidol and demonstrate that haloperidol inhibits the aggregation of LAMTOR1 and NLRP3. Since NLRP3 inflammasome activation has been implicated in gout, these data provide a foundation for exploring haloperidol as a potential therapy.

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