{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:55:08Z","timestamp":1790618108561,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T00:00:00Z","timestamp":1775433600000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272209"],"award-info":[{"award-number":["82272209"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sepsis\u2010induced intestinal injury is a severe complication associated with dysfunction affecting multiple organ systems and a significantly elevated risk of death. Intestinal barrier dysfunction plays a central role, but the underlying molecular pathways remain incompletely understood. The present study sought to explore how the Gzma\/GEF\u2010H1\/RhoA signalling axis contributes to the disruption of the intestinal epithelial barrier in sepsis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Transcriptomic data, clinical samples, and a murine caecal ligation and puncture (CLP) model was used to assess Gzma expression and its correlation with disease severity. We investigated how Gzma\u2014released by activated immune cells\u2014affects epithelial structure and function using in vitro co\u2010culture assays. These experiments assessed key tight junction proteins (occludin, claudin\u20101, ZO\u20101, E\u2010cadherin), transepithelial electrical resistance (TEER), and paracellular permeability. GEF\u2010H1 knockout mice and the GEF\u2010H1 activator plinabulin were employed to evaluate the physiological roles of GEF\u2010H1. Mutagenesis revealed how Gzma activates GEF\u2010H1. High\u2010throughput screening identified a GEF\u2010H1 modulator, and its efficacy was validated in septic mice. Gzma expression was significantly elevated during sepsis and correlated with disease severity. Gzma secretion from immune cells impaired the epithelial barrier by downregulating tight junction proteins, increasing permeability, and reducing TEER. Gzma activates GEF\u2010H1 by dephosphorylating Ser886, triggering the RhoA\/ROCK pathway and subsequent phosphorylation of MLC2, LIMK, and cofilin\u2014driving cytoskeletal remodelling. GEF\u2010H1 knockout mice showed reduced intestinal injury, higher survival rates, and intact barrier function; conversely, GEF\u2010H1 activation worsened intestinal damage. High\u2010throughput screening identified Epothilone A as a potent GEF\u2010H1 modulator that restores intestinal barrier integrity and improves survival in murine sepsis by suppressing the GEF\u2010H1\/librariesRhoA pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This research uncovers the Gzma\/GEF\u2010H1\/RhoA signalling axis as a pivotal contributor to intestinal barrier dysfunction during sepsis. GEF\u2010H1 represents a promising therapeutic target, and its inhibition by agents such as Epothilone A may offer a novel strategy for treating sepsis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Gzma induces the dephosphorylation of Ser886 on GEF\u2010H1, activating the RhoA\/ROCK pathway and disrupting the intestinal epithelial barrier.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Knocking out GEF\u2010H1 can alleviate intestinal damage, protect multiple organs, and increase the survival rate of septic mice.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Epothilone A inhibits the activation of GEF\u2010H1, thereby restoring the barrier function and reducing the mortality rate of sepsis.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70651","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T05:00:02Z","timestamp":1775538002000},"source":"Crossref","is-referenced-by-count":2,"title":["Mechanism of Gzma\u2010mediated GEF\u2010H1 activation in intestinal epithelial cells leading to intestinal barrier dysfunction in sepsis"],"prefix":"10.1002","volume":"16","author":[{"given":"Zexing","family":"Lin","sequence":"first","affiliation":[{"name":"Department of General Surgery Nanjing BenQ Medical Center The Affiliated BenQ Hospital of Nanjing Medical University  Nanjing China"},{"name":"Department of Surgical Research Laboratory Nanjing BenQ Medical Center The Affiliated BenQ Hospital of Nanjing 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