{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T01:48:03Z","timestamp":1793929683779,"version":"4.8.0"},"reference-count":50,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T00:00:00Z","timestamp":1722902400000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273993 82200658"],"award-info":[{"award-number":["82273993 82200658"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>As the leading cause of end\u2010stage liver disease, nonalcoholic fatty liver disease (NAFLD) is mainly induced by lipid dyshomeostasis. The translation of endogenous circular RNAs (circRNAs) is closely related to the progression of various diseases, but the involvement of circRNAs in NAFLD has not been determined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Combined high\u2010throughput circRNA profiles were used to identify circRNAs with translational potential. The underlying molecular mechanisms were investigated by RNA sequencing, pull\u2010down\/MS and site\u2010specific mutagenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In this study, we focused on circ\u2010SLC9A6, an abnormally highly expressed circRNA in human and mouse liver tissue during NAFLD development that exacerbates metabolic dyshomeostasis in hepatocytes by encoding a novel peptide called SLC9A6\u2010126aa in vivo and in vitro. YTHDF2\u2010mediated degradation of m6A\u2010modified circ\u2010SLC9A6 was found to be essential for the regulation of SLC9A6\u2010126aa expression. We further found that the phosphorylation of SLC9A6\u2010126aa by AKT was crucial for its cytoplasmic localization and the maintenance of physiological homeostasis, whereas high\u2010fat stress induced substantial translocation of unphosphorylated SLC9A6\u2010126aa to the nucleus, resulting in a vicious cycle of lipid metabolic dysfunction. Nuclear SLC9A6\u2010126aa promotes transcriptional activation of the target gene CD36 and enhances its occupancy of the CD36 promoter locus by regulating MOF\u2010mediated histone H4K16 acetylation. Hepatic CD36 depletion significantly ameliorated hyperactivated MAPK signalling and lipid disturbance in SLC9A6\u2010126aa transgenic mice. Clinically, increasing levels of SLC9A6\u2010126aa were observed during NAFLD progression and were found to be positively correlated with the CD36 and MAPK cascades.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study revealed the role of circ\u2010SLC9A6\u2010derived SLC9A6\u2010126aa in the epigenetic modification\u2010mediated regulation of lipid metabolism. Our findings may provide promising therapeutic targets for NAFLD and new insights into the pathological mechanisms of metabolic diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Under normal circumstances, driven by m6A modification, YTHDF2 directly recognizes and degrades circ\u2010SLC9A6, thereby inhibiting the translation of SLC9A6\u2010126aa.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Additionally, AKT1 phosphorylates and inhibits the nuclear translocation of SLC9A6\u2010126aa.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>In NAFLD, lipid overload leads to YTHDF2 and AKT1 deficiency, ultimately increasing the expression and nuclear import of SLC9A6\u2010126aa.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Nuclear SLC9A6\u2010126aa binds directly to the CD36 promoter and initiates CD36 transcription, which induces lipid dyshomeostasis.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.1801","type":"journal-article","created":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T23:49:55Z","timestamp":1722988195000},"source":"Crossref","is-referenced-by-count":26,"title":["A novel peptide encoded by circ\u2010SLC9A6 promotes lipid dyshomeostasis through the regulation of H4K16ac\u2010mediated CD36 transcription in NAFLD"],"prefix":"10.1002","volume":"14","author":[{"given":"Yue","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacology Dalian Medical University  Dalian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyao","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Surgery Division of Hepatobiliary and Pancreatic Surgery The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"},{"name":"Department of Surgery Division of Hepatobiliary and Pancreatic Surgery The First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhecheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Dalian Medical University  Dalian 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