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Exposure to DNA\u2010damaging agents such as ionizing radiation is another risk factor for HCC; calorie restriction (CR), however, effectively delays the onset of radiation\u2010induced HCC. We investigated whether NASH is relevant to radiation\u2010induced HCC and the cancer\u2010preventing effect of CR. Eight\u2010day\u2010old male B6C3F1 mice were irradiated with 3.8\u2009Gy of X\u2010rays and then fed a standard diet or 30% CR diet from 49\u2009days of age until necropsy, which was performed from 56 to 600\u2009days with ~100\u2010day intervals to assess both pathological changes and gene expression levels. We found that early\u2010life exposure to radiation accelerated lipid accumulation and NASH\u2010like histopathological changes in the liver, accompanied by accelerated development of HCC. CR ameliorated the changes in lipid metabolism in the liver and reversed the NASH\u2010like pathology, which effectively delayed HCC development. Gene\u2010expression profiling revealed the radiation\u2010related activation and CR\u2010related suppression of the peroxisome proliferator\u2010activated receptor gamma\/Cd36 pathway of transmembrane fatty\u2010acid translocation before development of the NASH\u2010like state. Thus, early\u2010life exposure to radiation affects lipid metabolism and induces a steatoinflammatory microenvironment that favors HCC development. Therefore, targeting this pathway by CR (or measures that mimic CR) may be a promising strategy for preventing HCC caused by either radiation or other DNA\u2010damaging agents.<\/jats:p>","DOI":"10.1002\/ijc.34651","type":"journal-article","created":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T09:19:40Z","timestamp":1689585580000},"page":"1529-1542","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Ionizing radiation promotes, whereas calorie restriction suppresses, <scp>NASH<\/scp> and hepatocellular carcinoma in mice"],"prefix":"10.1002","volume":"153","author":[{"given":"Yi","family":"Shang","sequence":"first","affiliation":[{"name":"Department of Radiation Effects Research National Institute of Radiological Sciences (NIRS), National Institutes for Quantum Science and Technology (QST)  Chiba 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