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BackgroundHuman blood metabolites have demonstrated close associations with thyroid disorders in observational studies. However, it’s essential to determine whether these correlations imply causation. Mendelian Randomization (MR) offers a promising approach to investigate these patterns.AimsThe primary aim of our investigation is to establish causality between blood metabolites and three thyroid disorders: TC, GD, and HT.MethodsWe employed a two-sample bidirectional MR analysis approach to assess the relationships between 452 blood metabolites and the three aforementioned thyroid disorders. Causal links were estimated using the IVW method, with sensitivity analyses conducted via MR-Egger, Weighted Median, and MR-PRESSO. We assessed potential heterogeneity and pleiotropy using MR-Egger intercept and Cochran’s Q statistic. Additionally, we conducted pathway analysis to identify potential metabolic pathways.ResultsWe found 46 metabolites that showed suggestive associations with thyroid disease risk, especially Aspartate (ORIVW=7.41; 95%CI: 1.51-36.27; PIVW=0.013) and C-glycosyltryptophan (ORIVW=0.04; 95%CI: 0.00–0.29; PIVW=0.001) impacted TC, Kynurenine (ORIVW=2.69; 95%CI: 1.08–6.66; PIVW=0.032) and 4-androsten-3beta,17beta-diol disulfate 2 (ORIVW=0.78; 95%CI: 0.48–0.91; PIVW=0.024) significantly impacted GD, and Alpha-ketoglutarate (ORIVW=46.89; 95%CI: 4.65–473.28; PIVW=0.001) and X-14189–leucylalanine (ORIVW=0.31; 95%CI: 0.15–0.64 PIVW=0.001) significantly impacted HT. We also detected 23 metabolites influenced by TC and GD. Multiple metabolic pathways have been found to be involved in thyroid disease.ConclusionOur MR findings suggest that the identified metabolites and pathways can serve as biomarkers for clinical thyroid disorder screening and prevention, while also providing new insights for future mechanistic exploration and drug target selection.

Being encoded by hepatitis B, hepatitis B X (HBx) protein plays crucial roles in hepatitis B-related hepatocellular carcinoma (HCC) occurrence, development, and metastasis. miRNAs also function in the progression of hepatitis B-related HCC. Hence, the objective of this study was to explore the impacts of miR-3677-3p on tumor progression and sorafenib resistance in hepatitis B-related HCC and the related underlying mechanisms. Our research revealed that miR-3677-3p and FOXM1 was up-regulated and FBXO31 was down-regulated in HBV+ HCC cells and tumor tissues from nude mice. After miR-3677-3p overexpression, cell proliferative, invasive, and migrating potentials and stemness-related protein (CD133, EpCAM, and OCT4) levels were enhanced, and cell apoptosis was reduced in Huh7 + HBx/SR cells and HepG2.2.15/SR cells. Besides, miR-3677-3p promoted the drug resistance of Huh7 + HBx/SR cells and HepG2.2.15/SR cells to sorafenib and lifted IC50. In vivo experiments, miR-3677-3p down-regulation suppressed the tumor growth in the hepatitis B HCC nude mouse models. Mechanistically, miR-3677-3p targeted and negatively-regulated FBXO31 and FBXO31 could enrich FOXM1 protein. miR-3677-3p down-regulation or FBXO31 overexpression promoted the ubiquitylation of FOXM1. In a word, miR-3677-3p bound to FBXO31 and inhibited FBXO31 expression, thus curtailing the ubiquitylation degradation of FOXM1, contributing to HCC development and sorafenib resistance. [ABSTRACT FROM AUTHOR]