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This study aimed to investigate the effects of OR and its rate\u2010limiting enzyme, ornithine decarboxylase 1 (ODC1), on lipid metabolism using high\u2010fat diet (HFD)\u2013induced obese C57BL\/6 mice and C3H10T1\/2 cell models. The results showed that OR supplementation and ODC1 overexpression exerted similar effects, including significantly aggravated HFD\u2010induced obesity, elevated serum polyamine levels, impaired glucose tolerance, reduced oxygen consumption, and hepatic steatosis. Transcriptomic analysis combined with protein validation indicated that ODC1\u2010promoted lipid deposition is associated with suppression of the AMPK\/ACC pathway. In\u00a0vitro, ODC1 overexpression promoted adipocyte proliferation and differentiation, accompanied by elevated levels of polyamines, including putrescine, spermidine, and spermine. Increased polyamine turnover further induced polyamine catabolic enzymes spermidine\/spermine N1\u2010acetyltransferase 1 (SAT1) and polyamine oxidase (PAOX), resulting in increased reactive oxygen species (ROS) accumulation, lipid peroxidation, and mitochondrial dysfunction. These changes were associated with suppression of the AMPK\/ACC pathway, resulting in increased intracellular triglyceride (TG) accumulation. Conversely, treatment with the ODC1 inhibitor DFMO or knockdown ODC1 markedly alleviated oxidative stress and lipid accumulation. Furthermore, OR supplementation failed to reverse oxidative stress and adipogenesis following ODC1 knockdown, indicating that its metabolic effects are largely dependent on ODC1 activity. Taken together, our findings reveal that ODC1\u2010mediated polyamine synthesis links SAT1\/PAOX\u2010associated ROS production to AMPK\/ACC and increased lipid accumulation, highlighting ODC1 as a potential therapeutic target for obesity and lipid metabolic disorders.<\/jats:p>","DOI":"10.1096\/fj.202600340rr","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T11:56:21Z","timestamp":1782906981000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>ODC1<\/scp>\n                    \u2010Mediated Ornithine Metabolism Exacerbates Obesity by Disrupting\n                    <scp>AMPK<\/scp>\n                    \/\n                    <scp>ACC<\/scp>\n                    Pathway"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2612-7444","authenticated-orcid":false,"given":"Shouyuan","family":"Wang","sequence":"first","affiliation":[{"name":"College of Animal Science Shanxi Agricultural University  Taiyuan Shanxi P. 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