Epresent attractive non-invasive biomarkers to accurately diagnose and monitor NAFLD and liver fibrosis . Distinct miRNA panels for NAFLD diagnosis have been proposed [23,175,209] and, when validated, they could hopefully replace liver biopsy, that is still the mainstay of diagnosis and monitoring of NAFLD, though SIRT1 Modulator review limited by its invasiveness, expensiveness and risk of complications [208,210]. Almost all the diagnostic panels proposed for NAFLD incorporate miR-122, as the most widely studied liver-specific miRNA, with 75 sensitivity and specificity above 80 [21,182,211]. Precise miRNAs signature could also be utilized as danger estimation of improved or worse prognosis, and to predict efficacy in therapeutic interventions. Indeed, it has been shown that weight-loss interventions, particularly bariatric surgery, and antidiabetic drugs could modify miRNA expression profiles [32,one hundred,158]. Assessment of lncRNAs as biomarkers for pre-diabetes and T2D is ongoing. One example is, growth arrest particular 5 (GAS5) has been suggested as a prognostic biomarker, as decreased GAS5 MMP-1 Inhibitor Storage & Stability levels improve the threat of developing diabetes. Similarly, ENST00000550337.1 levels can be capable to differentiate amongst pre-diabetes and T2D, and circulating H19 levels look to discriminate sufferers with much better glycemic handle from these with poorly controlled diabetes [37,212]. Many lncRNAs have also been involved in liver disease and have already been connected with NAFLD improvement and progression . Current expertise around the part of circRNAs in IR-related illnesses is fairly limited. Nonetheless, preliminary data around the contribution of circRNAs in pathophysiology of diabetes and its related cardiovascular complication, have encouraged to explore circRNA profiles, both in tissue and blood, as valid biomarker for the diagnosis and prognosis of diabetes . As an illustration, several authors demonstrated the potential use of circ-0054633 as low-cost, particular and sensitive diagnostic biomarker for prediabetes and T2D, as circulating levels of this circRNAs steadily elevated from normoglycemia to pre-diabetes upInt. J. Mol. Sci. 2021, 22,19 ofto T2D [198,213]. Other circRNAs have been recommended as predictive biomarker of microand macrovascular complications in diabetic patients. As for NAFLD, current findings recommend that aberrant signaling of circRNA_0046367 and circRNA_0046366/miR-34a/PPAR might be involved in steatosis and could represent a therapeutic target in NAFLD therapy . Other studies recognize other circRNAs related with hepatic steatosis, including circScd1–significantly reduced in NAFLD–and the circRNA_021412/miR-1972/LPIN1 signaling pathway, involved in liver metabolism and, potentially, in steatosis [13,21,214]. Aside from their potential application as diagnostic biomarkers, ncRNAs have also been investigated as therapeutic targets . Certainly, the relevance of ncRNAs as transcription elements tends to make them appropriate as therapeutic agents, exploiting their gene silencing prospective . Basically, miRNA agonists and antagonists could represent fascinating therapeutic tools, to restore altered miRNA expression in specific tissues . In case of downregulation of miRNA, a therapeutic method would be represented by transfection of synthetic miRNA mimetics (miRNA mimics) or plasmid/viral vectors, to achieve a pharmacological activation of miRNA function, whereas in case of miRNAs overexpression, the therapeutic approach would be to transfect certain synthetic an.