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Autophagy is an organized form of intracellular degradation process that eliminates damaged organelles and proteins. Reticulophagy (ER\u2010phagy) is a selective type of autophagy in which a portion of the endoplasmic reticulum (ER) is sequestered and degraded within an autophagosome. ER\u2010phagy is triggered by excessive ER\u2010associated degradation levels resulting from an increased load of misfolded proteins. FAM134B has been identified as a mammalian ER\u2010phagy receptor. Dysregulation of autophagy plays a crucial role in the progression of NAFLD. 5\u2032\u2010Adenosine monophosphate\u2010activated protein kinase (AMPK), an energy sensor molecule, is downregulated in NAFLD and other metabolic diseases. Given the potential relationship between AMPK activation and autophagy induction, we investigated whether AMPK activation could ameliorate steatosis by inducing autophagy. In this study, palmitate (PA) was used to induce steatosis in HepG2 cells, and AMPK activation was studied using 5\u2010aminoimidazole\u20104\u2010carboxamide\u20101\u2010\u2010\n                    <jats:sc>d<\/jats:sc>\n                    \u2010ribofuranoside (AICAR). PA treatment of HepG2 cells decreased cell viability and mitochondrial membrane potential (MMP) and increased the generation of reactive oxygen species (ROS), thereby leading to the accumulation of lipids. The mRNA expression of autophagy proteins Beclin 1 and LC3B was downregulated following PA treatment. The protein expression of p\u2010AMPK, Beclin 1, and FAM134 was downregulated, while the expression of p62 was upregulated upon PA treatment in HepG2 cells. AICAR treatment of PA\u2010induced HepG2 cells reversed the changes induced by PA. The protective effects of AICAR in PA\u2010induced cytolipotoxicity may offer new insights for improving the treatment options for NAFLD.\n                  <\/jats:p>","DOI":"10.1002\/bab.70094","type":"journal-article","created":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T05:41:07Z","timestamp":1763790067000},"page":"1281-1294","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["5\u2010Aminoimidazole\u20104\u2010carboxamide\u20101\u2010\u03b2\u2010\n                    <scp>d<\/scp>\n                    \u2010ribofuranoside ameliorates lipotoxicity through enhanced reticulophagy in HepG2 cells"],"prefix":"10.1002","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4746-5553","authenticated-orcid":false,"given":"Ajay","family":"Krishnan U","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biotechnology, Faculty of Science Annamalai University  Annamalai Nagar Tamil Nadu 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