(20S) Ginsenoside Rh2 Exerts Its Anti-Tumor Effect by Disrupting the HSP90A-Cdc37 System in Human Liver Cancer Cells.

(20S) ginsenoside Rh2 (G-Rh2), a major bioactive metabolite of ginseng, effectively inhibits the survival and proliferation of human liver cancer cells. However, its molecular targets and working mechanism remain largely unknown. Excitingly, we screened out heat shock protein 90 alpha (HSP90A), a key regulatory protein associated with liver cancer, as a potential target of (20S) G-Rh2 by phage display analysis and mass spectrometry. The molecular docking and thermal shift analyses demonstrated that (20S) G-Rh2 directly bound to HSP90A, and this binding was confirmed to inhibit the interaction between HSP90A and its co-chaperone, cell division cycle control protein 37 (Cdc37). It is well-known that the HSP90A-Cdc37 system aids in the folding and maturation of cyclin-dependent kinases (CDKs). As expected, CDK4 and CDK6, the two G0-G1 phase promoting kinases as well as CDK2, a key G1-S phase transition promoting kinase, were significantly downregulated with (20S) G-Rh2 treatment, and these downregulations were mediated by the proteasome pathway. In the same condition, the cell cycle was arrested at the G0-G1 phase and cell growth was inhibited significantly by (20S) G-Rh2 treatment. Taken together, this study for the first time reveals that (20S) G-Rh2 exerts its anti-tumor effect by targeting HSP90A and consequently disturbing the HSP90A-Cdc37 chaperone system. HSP90A is frequently overexpressed in human hepatoma cells and the higher expression is closely correlated to the poor prognosis of liver cancer patients. Thus, (20S) G-Rh2 might become a promising alternative drug for liver cancer therapy.

A novel EIF3C-related CD8+ T-cell signature in predicting prognosis and immunotherapy response of nasopharyngeal carcinoma.

PURPOSE: At present, dysfunctional CD8+ T-cells in the nasopharyngeal carcinoma (NPC) tumor immune microenvironment (TIME) have caused unsatisfactory immunotherapeutic effects, such as a low response rate of anti-PD-L1 therapy. Therefore, there is an urgent need to identify reliable markers capable of accurately predicting immunotherapy efficacy. METHODS: Utilizing various algorithms for immune-infiltration evaluation, we explored the role of EIF3C in the TIME. We next found the influence of EIF3C expression on NPC based on functional analyses and RNA sequencing. By performing correlation and univariate Cox analyses of CD8+ Tcell markers from scRNA-seq data, we identified four signatures, which were then used in conjunction with the lasso algorithm to determine corresponding coefficients in the resulting EIF3C-related CD8+ T-cell signature (ETS). We subsequently evaluated the prognostic value of ETS using univariate and multivariate Cox regression analyses, Kaplan-Meier curves, and the area under the receiver operating characteristic curve (AUROC). RESULTS: Our results demonstrate a significant relationship between low expression of EIF3C and high levels of CD8+ T-cell infiltration in the TIME, as well as a correlation between EIF3C expression and progression of NPC. Based on the expression levels of four EIF3C-related CD8+ T-cell marker genes, we constructed the ETS predictive model for NPC prognosis, which demonstrated success in validation. Notably, our model can also serve as an accurate indicator for detecting immunotherapy response. CONCLUSION: Our findings suggest that EIF3C plays a significant role in NPC progression and immune modulation, particularly in CD8+ T-cell infiltration. Furthermore, the ETS model holds promise as both a prognostic predictor for NPC patients and a tool for adjusting individualized immunotherapy strategies.

Correlation between thyroid function, sensitivity to thyroid hormones and metabolic dysfunction-associated fatty liver disease in euthyroid subjects with newly diagnosed type 2 diabetes.

PURPOSE: To estimate the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and to evaluate the associations between thyroid parameters, MAFLD and liver fibrosis in euthyroid patients with newly diagnosed type 2 diabetes mellitus (T2DM). METHODS: Overall, 776 patients with newly diagnosed T2DM and 120 subjects without diabetes were included. All the participants were euthyroid, and were categorized as non-MAFLD and MAFLD. Demographic information, biochemical parameters, and serum thyroid hormones were collected. The thyroid hormone sensitivity indices were calculated. MAFLD was defined according to abdominal ultrasound and clinical manifestations. Noninvasive fibrosis indices were calculated to identify advanced liver fibrosis. RESULTS: The prevalence of MAFLD was significantly higher in patients with T2DM than in subjects without diabetes. Levels of free triiodothyronine (FT3) and FT3 to free thyroxine (FT4) ratio were significantly higher in subjects with MAFLD. In patients with T2DM, levels of thyroid stimulating hormone (TSH), Thyroid feedback quantile-based index (TFQIFT3) calculated using FT3 and TSH, thyrotroph T3 resistance index (TT3RI) and thyrotroph T4 resistance index (TT4RI) were significantly higher in subjects with MAFLD. The prevalence of MAFLD increased with the rise of FT3, FT3/FT4, TSH, and sensitivity to thyroid hormone indices (TFQIFT3, TT3RI, and TT4RI). But significant correlations were not found between thyroid hormones, sensitivity to thyroid hormones and MAFLD, after adjustment for BMI and HOMA-IR. The incidence of advanced fibrosis tended to increase as the rise of TSH and sensitivity to thyroid hormone indices (TFQIFT3, TT3RI, TT4RI, and TSHI). CONCLUSION: MAFLD was prevalent in euthyroid patients with newly diagnosed T2DM. Higher normal FT3, TSH and impaired sensitivity to thyroid hormones are associated with increased incidence of MAFLD, being dependent on other metabolic factors.