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This study aimed to investigate the potential protective effects of AO\u2010I against lipotoxicity in both cultured hepatocytes and mice with non\u2010alcoholic fatty liver disease (NAFLD). The NAFLD model was established by feeding C57BL\/6 mice a high\u2010fat diet (HFD) for 12\u2009weeks. Oral administration of AO\u2010I at doses of 20 or 50\u2009mg\/kg body weight per day was explored. Lipotoxicity in AML12 hepatocytes was induced by incubation with palmitate for in\u00a0vitro investigations on the roles of AO\u2010I. The results demonstrated that supplementation with AO\u2010I improved alanine transaminase (ALT), aspartate transaminase (AST), and liver histology in NAFLD mice. Furthermore, AO\u2010I directly alleviated palmitate\u2010induced lipotoxicity by reducing hepatocyte death. Mechanistic studies revealed that AO\u2010I significantly attenuated lipotoxicity through its potential resistance to endoplasmic reticulum (ER) stress and IRE1\u03b1\u2010XBP1 splicing both in\u00a0vivo and in\u00a0vitro. We identified that AO\u2010I substantially rescued HFD\u2010 and palmitate\u2010induced SIRT1 decline in mouse livers and hepatocytes, respectively, thereby improving liver injury and hepatocyte cell death. Mechanistic studies demonstrated that the amelioration of ER stress and lipotoxicity by AO\u2010I supplementation depended on SIRT1 activity. Moreover, AO\u2010I also mitigated IRE1\u03b1 activation\u2010triggered JNK\/p38 MAPK hyperphosphorylation. In conclusion, our findings suggest that AO\u2010I exhibits significant therapeutic effects for improving lipotoxicity in the liver and may be considered as a candidate for NAFLD therapy.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70406","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T01:02:38Z","timestamp":1783386158000},"page":"5758-5771","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Atractylenolide\n                    <scp>I<\/scp>\n                    Alleviates Lipotoxicity in Hepatocytes and Protects\n                    <scp>NAFLD<\/scp>\n                    in Mice Through\n                    <scp>SIRT1<\/scp>\n                    \u2010Dependent\n                    <scp>IRE1\u03b1<\/scp>\n                    \u2010\n                    <scp>XBP1<\/scp>\n                    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