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Upon inflammatory stimulation, phosphorylation at S701 (p-S701) sequestered Y705 phosphorylation (p-Y705) by interfering with the access of Janus kinase 1\/2 and restricting STAT3 overactivation. In contrast, the STAT3_\u0394S701 isoform was hyperactive because of the absence of this self-restricting mechanism. Deletion of S701 in mice increased susceptibility to colonic inflammation and tumorigenesis. Pharmacological inhibition of PP2A sustained p-S701 and alleviated colon inflammation in wild-type but not in \u0394S701 mice. Our findings highlight the importance of STAT3 heterogeneity in colonic inflammation and colorectal cancer.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adu8484","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T18:58:18Z","timestamp":1765393098000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["A hyperactive splice variant of STAT3 promotes colonic inflammation-associated tumorigenesis in mice"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4179-4009","authenticated-orcid":true,"given":"Meng","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Pesticide &amp; Chemical Biology of Ministry of Education, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, 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