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

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-1beta; 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. ### Competing Interest Statement V.L.A, B.D.G., B.C.W, and S.W. are named as inventors on patent applications filed by the University of Virginia. ### Funding Statement This work was supported in part by the University of Virginia Strategic Investment Fund grant SIF 167. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.