Mendelian randomization (MR) was employed to investigate the causal relationships between immune cell phenotypes, hyperthyroidism (HD), and potential metabolic mediators. In this study, we acquired 731 immune cell phenotypes from genome-wide association studies (GWAS) (n = 18,622), HD data from the research by Handan Melike Dönertaş et al. (3,731 cases, 480,867 controls), and aggregated statistics of 1,400 blood metabolites from UK Biobank (n = 115,078). Bidirectional MR analysis was performed to explore the causal relationships between the immune cell phenotypes and HD, and two-sample and multi-variable MR were conducted to identify the potential plasma metabolites mediating in HD. In addition, sensitivity analyses were used to evaluate robustness, heterogeneity, and horizontal pleiotropy of results. Single-cell transcriptome-based exploration of potential key molecule and mechanism by which plasma metabolites regulated the immune cell differentiation in HD pathogenesis. Co-localization analysis was using single-cell eQTL (sc-eQTL) data with key molecule to probe genetically shared effects. Two-sample MRshowed that CD25 on naive-mature B cell, CD8 + NKT cell, and thymol sulfate level were found to have causal relationships with HD (P < 0.008). The causal relationship between thymol sulfate and HD were further validated in an independent cohort using the inverse-variance weighted (IVW). In addition, CD25 on naive-mature B cells and CD8 + NKT cells were both negatively correlated with thymol sulfate (P < 0.05). The results remained significant after MR-Egger and MR-PRESSO correction for horizontal pleiotropy and heterogeneity (P > 0.05). Multi-variable MR results showed that CD25 on naive-mature B cell and CD8 + NKT cell mediated 8.67% and 10.4% of the associations between thymol sulfate and HD, respectively. Moreover, thymol sulfate mediated the evolution of CD8 + NKT cells in the immune microenvironment, identifying PTPRC, PTK2B, KDM5A and TIGIT as the key participating molecules. Co-localization analysis showed that the key molecules had significant genetic sharing effects with CD8 + NKT cells (PPH4 > 0.75, R2 > 0.8, P < 0.05), with PTK2B having the broadest sharing interval. Current MR study provides evidence supporting causal relationships between several specific immune cell phenotypes and HD, as well as potential mediating metabolites. Thymol sulfate may increases the risk of HD pathogenesis by mediating the evolution of PTK2B genetic variants inducing CD8 + NKT cells in the progression of the immune microenvironment.

Although anaplastic thyroid cancer (ATC) constitutes only 1–2% of all thyroid malignancies, it is associated with an exceptionally high mortality rate, accounting for 14–39% of thyroid cancer-related deaths. In this study, we identified the critical role of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in ATC progression. Proteomic analysis revealed E-cadherin as a key mediator of PCSK9-driven malignancy in ATC. Mechanistically, PCSK9 promotes the degradation of E-cadherin through the lysosomal pathway. Furthermore, the loss of the p53 function, particularly the R248Q mutation, de-repressed PCSK9 expression at the transcriptional level. Notably, the PCSK9 inhibitor PF-846 considerably suppressed ATC proliferation and metastasis in both in vitro and in vivo models. In conclusion, PCSK9 enhances ATC malignancy by regulating E-cadherin degradation via the lysosomal pathway, underscoring its potential as a promising therapeutic target.

Rationale: Myxofibrosarcoma (MFS) is a subtype of soft tissue sarcoma that commonly occurs in the extremities but is rare in the neck. It is characterized by a high risk of local recurrence due to its specific infiltrative growth pattern. Patient concerns: A 56-year-old male presented with a large mass in the right neck with disability of the right upper limb. Diagnoses: Magnetic resonance imaging revealed a 12.48 × 9.01 × 14.16 cm mass with a “tail sign.” Resection with wide margins was performed to remove the tumor and the invaded surrounding tissues. Histopathological examination confirmed the diagnosis of high-grade MFS. Interventions: The patient developed local recurrence 24 months after surgery and died of the disease 26 months after the recurrence. Outcomes: This case presents the largest MFS located in the neck reported to date. The treatment of giant MFS in the neck is challenging due to the proximity of vital structures including vessels, nerves, and other tissues. The invasive pattern of MFS facilitates extensive spread into surrounding tissues, complicating complete surgical removal. And insufficient margins frequently result in disease recurrence. Lessons: This case highlights the significance of wide surgical margins in instances of extensive neck infiltration by MFS. However, further studies are required to confirm the specific margin values, and the advancement of effective adjuvant therapy is essential for improving patient survival.