{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T14:30:52Z","timestamp":1778509852764,"version":"3.51.4"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001868","name":"National Science Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001868","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Ste20-related protein proline\/alanine-rich kinase (SPAK) affects cell proliferation, differentiation, and transformation, and sodium and chloride transport in the gut. However, its role in gut injury pathogenesis is unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>We determined the role of SPAK in chemotherapy-induced intestinal mucositis using <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using SPAK-knockout (KO) mice, we evaluated the severity of intestinal mucositis induced by 5-fluorouracil (5-FU) by assessing body weight loss, histological changes in the intestinal mucosa, length of villi in the small intestine, pro-inflammatory cytokine levels, proliferative indices, and apoptotic indices. We also evaluated changes in gut permeability and tight junction-associated protein expression. Changes in cell permeability, proliferation, and apoptosis were assessed in SPAK siRNA-transfected 5FU-treated IEC-6 cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>5-FU-treated SPAK-KO mice exhibited milder intestinal mucositis, reduced pro-inflammatory cytokine expression, increased villus length, good maintenance of proliferative indices of villus cells, decreased apoptotic index of enterocytes, reduced gut permeability, and restoration of tight junction protein expression (<jats:italic>vs<\/jats:italic>. 5-FU-treated wild-type mice). Under <jats:italic>in vitro<\/jats:italic> conditions, siRNA-mediated SPAK-knockdown in IEC-6 cells decreased cell permeability and maintained homeostasis following 5-FU treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>SPAK deficiency attenuated chemotherapy-induced intestinal mucositis by modulating gut permeability and tight junction-associated protein expression and maintaining gut homeostasis in murine small intestinal tissues following gut injury. The expression of SPAK may influence the pathogenesis of chemotherapy-induced intestinal mucositis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2021.733555","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T11:39:50Z","timestamp":1638272390000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["SPAK Deficiency Attenuates Chemotherapy-Induced Intestinal Mucositis"],"prefix":"10.3389","volume":"11","author":[{"given":"Tien-Yu","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung-Sen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Len","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming-Hong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hsuan-Hwai","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung-Chun","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng-Jen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Lueng","family":"Shih","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Kuo","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsai-Yuan","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s1368-8375(98)00068-2","article-title":"Risk Factors Associated With Mucositis in Cancer Patients Receiving 5-Fluorouracil","volume":"34","author":"McCarthy","year":"1998","journal-title":"Oral Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)90696-7","article-title":"Efficacy of Adjuvant Fluorouracil and Folinic Acid in Colon Cancer. 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