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Calcium-activated neutral protease (calpain) dissociates cysteinyl aspartate specific proteinase-1 (caspase-1, cas-1) from the cytoskeleton, and the activated cas-1 is responsible for the production of N-terminus of gasdermin D (N-GSDMD), the final executor of pyroptosis. Blocking transient receptor potential vanilloid 4 (TRPV4) can reduce neuronal injury in temporal lobe epilepsy (TLE) model mice. This study investigated the role of TRPV4 in pyroptosis during TLE. In the hippocampus of pilocarpine-induced status epilepticus (PISE) mice, the ratio of inactive calpain 1 protein level to its total protein level (inactive\/total calpain 1) significantly decreased, while the ratio of inactive calpain 2 protein level to its total protein level remained unchanged. The protein levels of NLRP3, cleaved cas-1 (c-cas-1), interleukin (IL)-1\u03b2, and N-GSDMD increased, with more GSDMD-immunofluorescence-positive (GSDMD<jats:sup>+<\/jats:sup>) cells and fewer surviving pyramidal neurons observed in the hippocampus of PISE mice. Calpain inhibition with MDL-28170 reversed these changes, except for the elevated NLRP3 levels. Inhibitors targeting NLRP3 (MCC950) and cas-1 (Ac-YVAD-cmk) blocked the increase in c-cas-1, IL-1\u03b2, and N-GSDMD levels in the hippocampus of PISE mice. TRPV4 inhibition via HC-067047 increased the inactive\/total calpain 1 ratio, decreased NLRP3, c-cas-1, IL-1\u03b2, and N-GSDMD protein levels, reduced GSDMD<jats:sup>+<\/jats:sup> cells number, and improved pyramidal neuron survival in the hippocampus of PISE mice. Conversely, TRPV4 activation with GSK1016790A decreased the inactive\/total calpain 1 ratio, elevated NLRP3, c-cas-1, IL-1\u03b2, and N-GSDMD levels, and increased GSDMD<jats:sup>+<\/jats:sup> cells number in the hippocampus. In the hippocampus of GSK1016790A-injected mice, the inactive\/total calpain 1 ratio was increased by MDL-28170, and c-cas-1, IL-1\u03b2, and N-GSDMD protein levels were markedly attenuated by MDL-28170, MCC950, and Ac-YVAD-cmk, respectively. In conclusion, TRPV4 inhibition mitigates pyroptosis in PISE mice by downregulating the calpain 1\u2013NLRP3\/cas-1\u2013GSDMD pathway, ultimately reducing neuronal damage.<\/jats:p>","DOI":"10.1186\/s40478-025-01990-5","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T01:20:31Z","timestamp":1744248031000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Transient receptor potential vanilloid 4 blockage attenuates pyroptosis in hippocampus of mice following pilocarpine\u2011induced status epilepticus"],"prefix":"10.1186","volume":"13","author":[{"given":"Lihan","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guowen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Sha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimei","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9967-8987","authenticated-orcid":false,"given":"Chunfeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7382-8306","authenticated-orcid":false,"given":"Lei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,10]]},"reference":[{"issue":"3","key":"1990_CR1","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1046\/j.1471-4159.2000.741215.x","volume":"74","author":"DC Henshall","year":"2000","unstructured":"Henshall DC, Chen J, Simon RP (2000) Involvement of caspase-3-like protease in the mechanism of cell death following focally evoked limbic seizures. 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