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It has raised the concern that microgravity exposure can lead to liver dysfunction and metabolic syndromes. However, molecular mechanisms and intervention measures of the adverse effects of microgravity on hepatocytes are limited. In this study, we utilized the random positioning machine culture system to investigate the adverse effects on hepatocytes under simulated microgravity (SMG). Our results showed that SMG impaired hepatocyte viability, causing cell cycle arrest and apoptosis. Compared to normal gravity, it also triggered lipid accumulation, elevated triglyceride (TG) and ROS levels, and impaired mitochondria function in hepatocytes. Furthermore, RNA sequencing results showed that SMG upregulated genes implicated in lipid metabolisms, including PPAR\u03b3, PLIN2, CD36, FABPs, etc. Importantly, all these defects can be suppressed by melatonin, a potent antioxidant secreted by the pineal gland, suggesting its potential use of therapeutic intervention.<\/jats:p>","DOI":"10.1096\/fj.202301137r","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T11:23:39Z","timestamp":1691493819000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Melatonin ameliorates simulated\u2010microgravity\u2010induced mitochondrial dysfunction and lipid metabolism dysregulation in hepatocytes"],"prefix":"10.1096","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6637-568X","authenticated-orcid":false,"given":"Yue","family":"Xiong","sequence":"first","affiliation":[{"name":"Center for Energy Metabolism and Reproduction, 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