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Although macrophages are recognized as pivotal coordinators of hepatic tissue repair, the precise checkpoints governing their functional transitions during regeneration remain elusive. Here, we identify the glutamine transporter SLC1A5 (Solute Carrier Family 1 Member 5) as a critical metabolic gatekeeper of macrophage function during liver regeneration. Using a mouse model of partial hepatectomy, we show that SLC1A5 is markedly upregulated in monocyte-derived macrophages at the peak of regeneration. Myeloid specific deletion of\n                    <jats:italic>Slc1a5<\/jats:italic>\n                    (\n                    <jats:italic>Slc<\/jats:italic>\n                    1\n                    <jats:italic>a<\/jats:italic>\n                    5\n                    <jats:sup>fl\/fl<\/jats:sup>\n                    <jats:italic>Lyz<\/jats:italic>\n                    2\n                    <jats:sup>cre<\/jats:sup>\n                    ) severely impairs hepatocyte proliferation and diminishes the expression of macrophage derived regenerative factors. Mechanistically,\n                    <jats:italic>Slc1a5<\/jats:italic>\n                    deficiency depletes intracellular glutamine, which triggers macrophage senescence and drives a pro-inflammatory phenotype. This senescent state selectively downregulates\n                    <jats:italic>Gas6<\/jats:italic>\n                    (Growth Arrest Specific 6), a crucial bridging ligand for efferocytosis, thereby impairing apoptotic cell clearance and exacerbating local inflammation. Strikingly, exogenous\n                    <jats:italic>Gas6<\/jats:italic>\n                    , senolytic Quercetin therapy, or\u00a0in vivo\u00a0L-glutamine supplementation successfully alleviates macrophage senescence, reinstates Gas6 mediated efferocytosis, and rescues defective liver regeneration. Collectively, our findings reveal a novel \u2018\n                    <jats:italic>Slc1a5<\/jats:italic>\n                    -glutamine-senescence-efferocytosis\u2019 axis that dictates macrophage driven tissue repair. This study not only uncovers a fundamental immunometabolic mechanism but also highlights glutamine supplementation and senolytics therapy as promising clinically strategies to accelerate liver regeneration.\n                  <\/jats:p>","DOI":"10.1186\/s43556-026-00526-0","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:31:37Z","timestamp":1788233497000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Solute Carrier Family 1 Member 5 (SLC1A5)-dependent glutamine transport regulates macrophage senescence and efferocytosis during liver regeneration"],"prefix":"10.1186","volume":"7","author":[{"given":"Haoran","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyuan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangxi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Ling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangshuang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"issue":"6532","key":"526_CR1","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1126\/science.abg4864","volume":"371","author":"ER Andersson","year":"2021","unstructured":"Andersson ER. 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