{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:45:06Z","timestamp":1792611906243,"version":"4.5.0"},"reference-count":38,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"vor","delay-in-days":15,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K02692"],"award-info":[{"award-number":["JP24K02692"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP24K20712"],"award-info":[{"award-number":["JP24K20712"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Chronic metabolic stress is increasingly recognized as a driver of aging\u2010like tissue dysfunction, but whether it durably reprograms liver regenerative cells, potentially compromising tissue maintenance and repair, remains unknown. Here, we show that high\u2010fat diet (HFD)\u2013induced metabolic stress promotes a persistent senescence\u2010like state in the liver regenerative compartment. In male rats, chronic HFD feeding induced hepatic steatosis together with oxidative stress, inflammatory responses, and senescence\u2010associated changes. Following carbon tetrachloride\u2010induced liver injury, HFD\u2010fed animals exhibited reduced proliferative responses. To determine whether these abnormalities were durably retained within regenerative cell populations, we established liver organoids from control and HFD\u2010fed rats. HF\u2010derived organoids showed reduced formation efficiency and impaired serial propagation capacity outside the original metabolic environment. Senescence\u2010associated abnormalities, including increased senescence\u2010associated \u03b2\u2010galactosidase staining, reduced Lamin B1 staining, and decreased Ki67 positivity, remained detectable through Passage 3. Transcriptomic and functional analyses revealed mitochondrial dysfunction and enhanced oxidative and inflammatory responses. These organoids also exhibited enhanced lipid accumulation and inflammatory secretion following fatty acid challenge. Treatment with the mitochondria\u2010targeted antioxidant MitoQ reduced oxidative stress and inflammatory secretion, improved oxygen consumption, and partially restored organoid formation efficiency, supporting a functional contribution of mitochondrial dysfunction to regenerative impairment. Together, these findings support a model in which chronic metabolic stress leaves persistent senescence\u2010like dysfunction within the liver regenerative compartment, extending its consequences beyond abnormalities in mature liver tissue.<\/jats:p>","DOI":"10.1111\/acel.70769","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T07:05:11Z","timestamp":1792134311000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High\u2010Fat Diet\u2013Induced Metabolic Stress Durably Reprograms the Liver Regenerative Compartment Toward a Senescence\u2010Like State"],"prefix":"10.1111","volume":"25","author":[{"given":"Mirai","family":"Yamazaki","sequence":"first","affiliation":[{"name":"Department of Hygiene Fujita Health University School of Medicine  Toyoake 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