Abscisic acid ameliorates inflammation-related diseases by inhibiting NLRP3 inflammasome activation

The NLRP3 inflammasome has been implicated in the pathogenesis of various human diseases; however, no specific NLRP3-targeted therapies have yet been approved for routine clinical use. Abscisic acid (ABA), a well-characterized plant hormone, has recently demonstrated efficacy in alleviating both chronic and acute inflammation. Here, we show that ABA dose-dependently inhibits caspase-1 activation (CASP1 p20), interleukin-1β (IL-1β) secretion, and NLRP3 inflammasome assembly in macrophages. Mechanistically, we identified PDZD8 as a direct target of ABA. ABA-mediated activation of PDZD8 promotes a compensatory lysosomal enlargement, preserves lysosomal membrane integrity, and prevents stress-induced lysosomal rupture. In vivo, ABA markedly attenuates NLRP3-driven inflammation in mouse models of cerulein-induced acute pancreatitis, monosodium urate (MSU)-induced gouty arthritis. Together, these findings identify ABA as a candidate natural compound with potential therapeutic relevance in NLRP3-driven inflammatory diseases and a possible starting point for further preclinical investigation.