{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:12:01Z","timestamp":1790946721394,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011729","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000}}],"reference-count":77,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The National Key Research and Development Program of China","award":["2022YFF1000202"],"award-info":[{"award-number":["2022YFF1000202"]}]},{"name":"China Agriculture Research System of MOF and MARA","award":["CARS-40"],"award-info":[{"award-number":["CARS-40"]}]},{"DOI":"10.13039\/501100010982","name":"Philippine Council for Industry, Energy, and Emerging Technology Research and Development","doi-asserted-by":"publisher","award":["2024YFNH0025"],"award-info":[{"award-number":["2024YFNH0025"]}],"id":[{"id":"10.13039\/501100010982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized primarily by hepatocellular steatosis and lipid accumulation, which leads to hepatocyte apoptosis, autophagy, inflammation, and intracellular oxidative stress. NAFLD is recognized as one of the most prevalent and complex chronic liver diseases globally, with its occurrence and associated mortality rates rising swiftly each year. Due to the high similarity between chicken fatty liver syndrome (FLS) and NAFLD, as well as the easy availability of diseased chickens, the chicken is considered an ideal model for studying the pathogenesis of NAFLD. Previous studies have pinpointed several circular RNAs (circRNAs) implicated in the pathogenesis of NAFLD, yet the underlying functions and mechanisms of numerous circRNAs continue to remain elusive. In this experiment, we utilized circRNA sequencing of chicken livers to identify a novel circRNA, named circACACA, and discovered that it disrupts the metabolic homeostasis of lipids within hepatocytes. Consequently, this disruption leads to oxidative stress and the induction of autophagy, ultimately exerting an adverse effect on chicken liver health. Mechanistically, circACACA functions as a molecular sponge for miR-132b-5p and miR-101-2-5p to modulate the expression of the downstream CBFB\/PIM1 complex. Consequently, it influenced the activity of the AKT\/mTOR and PPAR-\u03b3 signaling pathways to perform its physiological functions. Crucially, we noticed substantial sequence similarity of circACACA across diverse species by comprehensively searching databases. Further, our research with a mouse model confirmed that the functional conservation of circACACA across livers of different species. Overall, this study built a mechanistic network for circACACA and confirmed its sequence conservation and functional relevance across various species. Our results not only provide new targets for the prevention and treatment of NAFLD but also present fresh perspectives for progress in healthy production of laying hens.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011729","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T18:44:23Z","timestamp":1766083463000},"page":"e1011729","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Circular RNA profiling revealed an evolutionarily conserved circACACA promotes liver lipid metabolism, oxidative stress, and autophagy disorder in a ceRNA manner"],"prefix":"10.1371","volume":"21","author":[{"given":"Jing","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunshun","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9546-5753","authenticated-orcid":true,"given":"Huadong","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"issue":"1","key":"pgen.1011729.ref001","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.cld.2013.09.018","article-title":"Obesity-associated nonalcoholic fatty liver disease","volume":"18","author":"Y Yilmaz","year":"2014","journal-title":"Clin Liver Dis"},{"key":"pgen.1011729.ref002","doi-asserted-by":"crossref","DOI":"10.1016\/j.jhep.2014.12.012","article-title":"NAFLD: a multisystem disease","volume":"62","author":"CD Byrne","year":"2015","journal-title":"J Hepatol"},{"issue":"2","key":"pgen.1011729.ref003","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1080\/03602532.2017.1293683","article-title":"Non-alcoholic fatty liver disease (NAFLD) - pathogenesis, classification, and effect on drug metabolizing enzymes and transporters","volume":"49","author":"E Cobbina","year":"2017","journal-title":"Drug Metab Rev"},{"issue":"3","key":"pgen.1011729.ref004","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1097\/MOL.0000000000000080","article-title":"Fatty acid sources and their fluxes as they contribute to plasma triglyceride concentrations and fatty liver in humans","volume":"25","author":"MM Jacome-Sosa","year":"2014","journal-title":"Curr Opin Lipidol"},{"issue":"7","key":"pgen.1011729.ref005","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"SL Friedman","year":"2018","journal-title":"Nat Med"},{"key":"pgen.1011729.ref006","first-page":"979515","article-title":"Gut microbiota: association with NAFLD and metabolic disturbances","volume":"2015","author":"E Lau","year":"2015","journal-title":"Biomed Res Int"},{"issue":"4","key":"pgen.1011729.ref007","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1002\/hep.21327","article-title":"Long-term follow-up of patients with NAFLD and elevated liver enzymes","volume":"44","author":"M Ekstedt","year":"2006","journal-title":"Hepatology"},{"issue":"4","key":"pgen.1011729.ref008","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.3382\/ps.0541075","article-title":"Lipid biosynthesis in the chick. 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