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While its roles in itch and skin inflammation are established, the physiological role of TRPV3 in the intestine remains relatively poorly understood. Topical application of a TRPV3 inhibitor, KM-001, has entered phase I clinical trials for the treatment of pruritus; however, its poor metabolic stability limits broader therapeutic application. Here, we show that the KM-001-derivative Colivin has comparable TRPV3-blocking activity, but enhanced metabolic stability and increased oral bioavailability. Cryo-EM and site-directed mutagenesis analyses established that Colivin binds to the vanilloid binding pocket of TRPV3, stabilizing one of two distinct non-conducting conformations. Oral administration of Colivin effectively suppressed DSS-induced ulcerative colitis (UC) in wild-type, but not Trpv3-deficient mice. Collectively, our findings establish TRPV3 inhibition as a novel therapeutic strategy for UC, offer key structural insights into the inhibition mechanism of TRPV3, and provide critical structural insights for the rational design of potent and selective TRPV3 inhibitors.<\/jats:p>","DOI":"10.1038\/s44318-026-00896-9","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T17:05:26Z","timestamp":1786640726000},"page":"6480-6500","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Orally available Colivin traps TRPV3 in an inactive state and suppresses intestinal inflammation"],"prefix":"10.1038","volume":"45","author":[{"given":"Yujing","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3969-4748","authenticated-orcid":false,"given":"Jiahui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinglian","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuxian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuchu","family":"Xi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaowen","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerui","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chu","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7597-549X","authenticated-orcid":false,"given":"Kai","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5676-841X","authenticated-orcid":false,"given":"Michael X","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9379-6988","authenticated-orcid":false,"given":"Jie","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2692-2949","authenticated-orcid":false,"given":"Zhengyu","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"896_CR1","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1107\/S2059798318006551","volume":"74","author":"PV Afonine","year":"2018","unstructured":"Afonine PV, Poon BK, Read RJ, Sobolev OV, Terwilliger TC, Urzhumtsev A, Adams PD (2018) Real-space refinement in PHENIX for cryo-EM and crystallography. 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