Background: N6-methyladenosine (m⁶A) modification is the most common chemical modification in mammalian mRNAs, and it plays important roles by regulating several cellular processes. Previous studies report that m⁶A is implicated in modulating tumorigenesis and progression. However, dysregulation of m⁶A modification and effect of m⁶A demethylase fat-mass and obesity-associated protein (FTO) on glucose metabolism has not been fully elucidated in papillary thyroid cancer (PTC). Methods: Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry were performed to explore the expression profile of FTO in PTC tissues and adjacent non-cancerous thyroid tissues. Effects of FTO on PTC glycolysis and growth were investigated through in vitro and in vivo experiments. Mechanism of FTO-mediated m⁶A modification was explored through transcriptome-sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-qPCR, luciferase reporter assays, RNA stability assay and RNA immunoprecipitation assay. Results: FTO expression was significantly downregulated in PTC tissues. Functional analysis showed that FTO inhibited PTC glycolysis and growth. Further analyses were conducted to explore FTO-mediated m⁶A modification profile in PTC cells and Apolipoprotein E (APOE) was identified as the target gene for FTO-mediated m⁶A modification using RNA-seq and MeRIP-seq. FTO knockdown significantly increased APOE mRNA m⁶A modification and upregulated its expression. FTO-mediated m⁶A modification of APOE mRNA was recognized and stabilized by the m⁶A reader IGF2BP2. The findings showed that APOE also promoted tumor growth through glycolysis in PTC. Analysis showed that FTO/APOE axis inhibits PTC glycolysis by modulating IL-6/JAK2/STAT3 signaling pathway. Conclusion: FTO acts as a tumor suppressor to inhibit tumor glycolysis in PTC. The findings of the current study showed that FTO inhibited expression of APOE through IGF2BP2-mediated m⁶A modification and may inhibit glycolytic metabolism in PTC by modulating IL-6/JAK2/STAT3 signaling pathway, thus abrogating tumor growth.

Cuproptosis is a novel programmed cell death that depends on copper. The role and potential mechanism of cuproptosis-related genes (CRGs) in thyroid cancer (THCA) are still unclear. In our study, we randomly divided THCA patients from the TCGA database into a training set and a testing set. A cuproptosis-related signature consisting of six genes (SLC31A1, LIAS, DLD, MTF1, CDKN2A, and GCSH) was constructed using the training set to predict the prognosis of THCA and was verified with the testing set. All patients were classified into low- and high-risk groups according to risk score. Patients in the high-risk group had a poorer overall survival (OS) than those in the low-risk group. The area under the curve (AUC) values for 5 years, 8 years, and 10 years were 0.845, 0.885, and 0.898, respectively. The tumor immune cell infiltration and immune status were significantly higher in the low-risk group, which indicated a better response to immune checkpoint inhibitors (ICIs). The expression of six cuproptosis-related genes in our prognostic signature were verified by qRT-PCR in our THCA tissues, and the results were consistent with TCGA database. In summary, our cuproptosis-related risk signature has a good predictive ability regarding the prognosis of THCA patients. Targeting cuproptosis may be a better alternative for THCA patients.

Recently, Delphi consensus proposed an overarching term steatotic liver disease (SLD), with various subcategories such as MASLD, MetALD and ALD. Our aim was to investigate the association between MASLD/MetALD/ALD and four intrahepatic and extrahepatic diseases (liver diseases, renal diseases, cardiovascular diseases, and cancers) in the UK Biobank cohort. By defining hepatic steatosis as image-derived phenotype (IDP)-PDFF >5.21%, we used data from the UK Biobank to diagnose MASLD/ MetALD/ALD. The odd ratio (OR) and the hazard ratio (HR) were calculated using the logistic regression modals and Cox regression models, respectively. Among 39,230 eligible individuals, 6,865 MASLD subjects, 2,379 MetALD subjects and 884 ALD subjects were diagnosed. The last follow-up time was October 13, 2023. Consistent with the logistic analyses, MASLD/MetALD/ALD were significantly associated with a higher risk of liver diseases (HR=3.04 [95%CI:2.60∼3.56], HR = 2.69 [95% CI: 2.12∼3.42] and HR =3.99 [95%CI:2.92∼5.45], respectively). Subjects with MASLD also had an increased higher risk of renal diseases (HR = 1.40 [95%CI:1.20∼1.64]) and subjects with ALD had an increased higher risk of cancers (HR = 1.36 [95%CI:1.15∼1.60]). It is the first study to report the association between MASLD, MetALD, ALD and common intrahepatic and extrahepatic diseases based on magnetic resonance imaging data-PDFF. We found that MASLD, MetALD and ALD were risk factors for liver diseases. Meanwhile, MASLD was also a risk factor for renal diseases and ALD was a risk factor for cancers.

Papillary thyroid carcinoma (PTC) undergoes dedifferentiation into aggressive poorly differentiated (PDTC) or anaplastic (ATC) carcinomas in 10–15% of cases, a process potentially driven by cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), though their spatiotemporal dynamics remain poorly understood. Resveratrol (Res), a natural compound, has shown anticancer potential by promoting redifferentiation and apoptosis while inhibiting oncogenic signaling, suggesting utility in countering PTC dedifferentiation. Using spatial transcriptomics (10× Visium) on three surgical specimens, we obtained 14,191 high-quality spots annotated via UMAP and Leiden clustering into seven cell types, including CAFs, T cells, B cells, and others. Comparative gene expression and functional enrichment analyses revealed CAFs in poorly differentiated regions exhibited heightened glycolytic activity, correlated with ZFP57 upregulation and PKM2 induction. Glycolysis was validated through immunofluorescence, Seahorse assays, glucose/lactate measurements, and ZFP57-PKM2 reporter assays. CAF-conditioned media promoted PTC proliferation, invasion, and dedifferentiation while reducing radioiodine uptake in co-culture models. In xenografts, ZFP57 overexpression increased tumor growth and impaired radioiodine retention, whereas Res suppressed ZFP57, restored differentiation, enhanced radioiodine avidity, and inhibited glycolysis. Mechanistically, CAF-secretated lactate activated TGF-β/Smad2/3 signaling, fostering dedifferentiation and malignancy. Resveratrol reversed these effects by targeting ZFP57, normalizing CAF metabolism, and restoring PTC differentiation, indicating a promising therapeutic strategy against PTC progression.

Immune cells are central mediators of the immune response and play critical roles in the pathogenesis and progression of liver diseases. Understanding the specific contributions of immune cells to liver disease progression is essential for developing targeted therapeutic strategies. In this study, we employed a two-sample Mendelian randomization (MR) approach to explore potential causal relationships between peripheral immune cell phenotypes and liver diseases, using genetic instrumental variables from large-scale genome-wide association studies (GWAS). Applying the inverse variance weighted (IVW) methods, we identified that monocyte count(odds ratio (OR) 0.81; 95% confidence interval (CI) 0.74–0.90; P = 5.95 × 10^− 5, P_FDR = 3.57 × 10^− 4), CD3⁻ lymphocyte/lymphocyte (OR 0.59, 95% CI 0.45–0.79; P = 3.29 × 10^− 4, P_FDR = 5.92 × 10^− 3) and SSC-A (Side Scatter Area) on Natural Killer (NK) cells (OR 0.89, 95% CI 0.82–0.95; P = 1.37 × 10^− 3, P_FDR = 0.0396) acted as protective factors against alcoholic liver disease. Similarly, the trait HLA DR⁺⁺ monocyte/monocyte was associated with a lower risk of autoimmune hepatitis (OR 0.56, 95% CI 0.41–0.79; P = 7.42 × 10^− 4, P_FDR = 0.0475). Conversely, an elevated blood monocytic Myeloid-Derived Suppressor Cells (MDSCs) count was associated with a higher risk of chronic hepatitis (OR 1.23, 95% CI 1.11–1.37; P = 1.13 × 10^− 4, P_FDR = 1.58 × 10^− 3). Similarly, higher levels of HLA DR on CD14⁻ CD16⁺ monocyte (OR 0.84, 95% CI 0.78–0.91; P = 2.07 × 10^− 5, P_FDR = 1.32 × 10^− 3) conferred lower risk for cirrhosis of liver. In hepatic failure, CD39⁺ resting CD4 regulatory T cell count (OR 0.85, 95% CI 0.79–0.92; P = 1.70 × 10^− 5, P_FDR = 5.25 × 10^− 3) played a protective role and CD28⁺ CD45RA− CD8^dim T cell/CD8^dim T cell (OR 1.14, 95% CI 1.06–1.22; P = 2.63 × 10^− 4, P_FDR = 0.0406) exhibited a risk function. Our findings highlight key immune pathways in liver disease progression and underscore potential immunomodulatory targets for future therapeutic interventions. Further research is warranted to clarify the mechanistic underpinnings of these associations.