{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:16:45Z","timestamp":1783657005975,"version":"3.55.0"},"reference-count":45,"publisher":"Wiley","issue":"33","license":[{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000},"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":["82372991"],"award-info":[{"award-number":["82372991"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82373430"],"award-info":[{"award-number":["82373430"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Liver metastases represent an urgent unmet medical need in the care of cancer due to a lack of effective therapies. This study reveals that pathological ammonia accumulation, resulting from dysregulation of ammonia removal processes, promotes the formation of a hepatic microenvironment favorable for metastatic colonization. Metabolomic and transcriptomic analyses suggest that tumoral metabolic reprogramming due to cancer cell\u2010intrinsic hyperactivation of the\n                    <jats:italic>de novo<\/jats:italic>\n                    pyrimidine biosynthesis pathway impairs the urea cycle and causes pathological ammonia accumulation. Utilizing tumor microenvironmental profiling and single\u2010cell RNA sequencing, subsequent analyses further reveal that ammonia accumulation remodels the hepatic stromal\u2010immune landscape by inducing hepatic stellate cell differentiation into metastasis\u2010associated fibroblasts (MAFs), suppressing\n                    <jats:italic>\n                      Ifi27l2a\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    monocyte\u2010macrophages, and expanding pro\u2010metastatic low\u2010density neutrophils (LDNs). Strikingly, the ammonia detoxifying agent L\u2010ornithine\u2010L\u2010aspartate (LOLA) potently promotes ammonia removal, thereby reshaping the hepatic microenvironment with decrease of MAFs and LDNs and increase of\n                    <jats:italic>\n                      Ifi27l2a\n                      <jats:sup>+<\/jats:sup>\n                    <\/jats:italic>\n                    monocyte\u2010macrophages, and reducing metastatic burden in liver metastasis mouse models. These results suggest that ammonia, a metabolic toxin, is required for the formation of the hepatic microenvironment favoring liver metastatic colonization, and highlight LOLA as a promising therapeutic strategy for treatment of liver metastasis by detoxifying pathological ammonia accumulation.\n                  <\/jats:p>","DOI":"10.1002\/advs.202521098","type":"journal-article","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T05:51:17Z","timestamp":1775281877000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ammonia Detoxification Inhibits Liver Metastasis by Reshaping Hepatic Microenvironment"],"prefix":"10.1002","volume":"13","author":[{"given":"Sumin","family":"Sun","sequence":"first","affiliation":[{"name":"Jiangsu Institute of Cancer Research, Jiangsu Cancer Hospital Affiliated Cancer Hospital of Nanjing Medical University Nanjing Jiangsu China"},{"name":"Department of Oncology The Affiliated 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