TRPA1 promotes overactive bladder progression by activating the NLRP3 inflammasome and driving pyroptosis.

Overactive bladder (OAB) is strongly linked to intravesical inflammatory responses. Transient receptor potential ankyrin-1 (TRPA1) is a key sensor and signaling molecule in bladder function, crucial for initiating and maintaining inflammation. However, the mechanisms underlying TRPA1-mediated inflammatory processes in OAB remain unclear. This study aims to elucidate the molecular mechanisms of TRPA1 and the contribution of inflammatory pathways to OAB. Elevated TRPA1 expression was observed in urinary sediment cells from OAB patients and in bladder tissues from OAB animal models. Mechanistically, TRPA1 drives the progression of OAB by activating the Nod-Like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome and triggering pyroptosis. Notably, treatment with HC-030031 effectively mitigated inflammatory responses and restored bladder function, whereas Nlrp3 overexpression negated these therapeutic benefits. Furthermore, TRPA1-mediated upregulation of NLRP3 was dependent on the transcription factors MAZ and SMAD3, highlighting a novel regulatory axis. Our findings establish TRPA1 as a pivotal mediator in the progression of OAB by activating the NLRP3 inflammasome and thereby inducing pyroptosis. Targeting TRPA1 or the NLRP3 signaling pathway represents a promising therapeutic strategy for OAB, offering new insights into disease management and potential improvements in patient outcomes.