{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:34:21Z","timestamp":1793255661696,"version":"4.5.0"},"reference-count":44,"publisher":"Wiley","issue":"20","license":[{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,10,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Obesity and its associated metabolic disorders have become major global public health challenges. Increasing evidence indicates that mitophagy plays a pivotal role in the pathogenesis of obesity and related metabolic diseases. This study aimed to investigate the role and underlying mechanisms of E3 ubiquitin ligase RNF126 in obesity and non\u2010alcoholic fatty liver disease (NAFLD). Using\n                    <jats:italic>Rnf126<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    mice fed a high\u2010fat diet (HFD), we found RNF126 deficiency markedly exacerbated body weight gain, elevated serum ALT and AST levels, inflammatory responses, apoptosis, and insulin resistance. Histological analysis with H&amp;E and Oil Red O staining revealed that RNF126 deficiency aggravated hepatic inflammatory cell infiltration, lipid droplet accumulation, and adipocyte hypertrophy in HFD\u2010fed mice. HFD feeding significantly inhibited RNF126 expression in liver and muscle. Moreover,\n                    <jats:italic>Rnf126<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    mice exhibited reduced oxygen consumption, carbon dioxide production and heat generation without changes in food intake. Mechanistically, qPCR and Western blot analyses demonstrated that RNF126 deficiency suppressed the mRNA and protein expression of UCP\u20101, SIRT1, and PGC\u20101\u03b1 in the liver and white adipose tissue, indicating impaired mitochondrial biogenesis. Moreover, the protein levels of cleaved PINK1, Parkin, and LC3 were reduced, while p62 expression was increased in the liver of\n                    <jats:italic>Rnf126<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    mice, indicating inhibited autophagic activity. Consistently, oxidative stress was significantly elevated, as evidenced by increased MDA levels and decreased SOD and GSH contents.\n                    <jats:italic>Rnf126<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    mice livers displayed obvious mitochondrial swelling and partial cristae disorganization with an increase of mtDNA expression. Mitochondrial complex\u2010III enzymatic activity, hepatic ATP, TOM20 protein expression and complex\u2010III subunit UQCRFS1 expression were substantially decreased in HFD\u2010fed\n                    <jats:italic>Rnf126<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    \/\n                    <jats:sup>\u2212<\/jats:sup>\n                    mice. At the cellular level, RNF126 overexpression in palmitic acid\u2010treated HepG2 cells restored cleaved PINK1, Parkin, and LC3 protein levels, while reducing p62 expression, indicating that RNF126 promotes mitophagy. Furthermore, ROS fluorescence assays showed that RNF126 overexpression attenuated intracellular ROS accumulation. Rescue experiments demonstrated that the protective effects of RNF126 on mitochondrial membrane potential, lipid accumulation, and mitophagy marker expression are dependent on its ubiquitin ligase activity. Overall, RNF126 alleviates HFD\u2010induced lipid accumulation and hepatic injury by promoting mitophagy and maintaining redox homeostasis, suggesting its potential as a novel therapeutic target for NAFLD.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600460r","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:28:43Z","timestamp":1792171723000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>E3<\/scp>\n                    Ubiquitin Ligase\n                    <scp>RNF126<\/scp>\n                    Contributes to Pathogenesis of Obesity by Induction Mitophagy Mediated by\n                    <scp>PINK1<\/scp>\n                    \/Parkin Pathway"],"prefix":"10.1096","volume":"40","author":[{"given":"Bing","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Endocrinology The First Affiliated Hospital of Soochow University  Suzhou Jiangsu 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