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Histological staining experiments were performed to evaluate liver injury. Flow cytometry and RNA sequencing analyses were conducted to investigate the effects of\n                      <jats:italic>Glul<\/jats:italic>\n                      deficiency on liver immunity. Additionally, several strategies were applied to intervene ALI in mice, including administration of CCL2 neutralising antibody or GS inhibitor L\u2010methionine sulfoximine (MSO), as well as adeno\u2010associated virus (AAV)\u2010mediated enhancement of GS expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The expression of\n                      <jats:italic>Glul<\/jats:italic>\n                      in myeloid cells was downregulated in wild\u2010type mice after ALI modelling by LPS\/D\u2010GalN. Moreover,\n                      <jats:italic>Glul<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u2206Lyz2<\/jats:italic>\n                      <\/jats:sup>\n                      mice demonstrated aggravated ALI and higher mortality upon LPS\/D\u2010GalN challenge, compared to the control\n                      <jats:italic>Glul<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>f\/f<\/jats:italic>\n                      <\/jats:sup>\n                      littermates. Notably,\n                      <jats:italic>Glul<\/jats:italic>\n                      deficiency significantly contributed to the activation of monocyte\u2010derived macrophages (MoMFs), secretion of C\u2010C chemokine ligand 2 (CCL2) and the recruitment of C\u2010C chemokine receptor 2\u2010positive monocytes. Treatment with CCL2 neutralising antibody significantly alleviated ALI by inhibiting MoMF activation. Interestingly, although MSO treatment effectively blocked the enzyme activity of GS, it exerted both preventive and therapeutic effects against ALI, which could be attributed to the elevation of GS protein level. Therefore, in\u00a0vivo global or myeloid GS was overexpressed via AAV delivery system, which demonstrated potent protective efficacy against ALI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study provided an updated look at the protective role of GS independent of its enzyme activity in ALI and shed light on the potential therapeutical strategies for ALI intervention.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/liv.70105","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T11:04:44Z","timestamp":1749726284000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Myeloid Glutamine Synthetase Protects Against Acute Liver Injury in Mice Independent of Its Enzyme 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