SLC8A1 as a novel susceptibility gene in facilitating tendinopathy: insights into its mechanisms from Mendelian randomization and experimental validation.

BACKGROUND: Patients with tendinopathy (TD) have expressed dissatisfaction with the efficacy of the first-line treatment, indomethacin. This research aims to identify key biomarkers in TD and investigate their underlying mechanisms. METHODS: Tendon samples were harvested from 5 Sprague-Dawley (SD) rats exhibiting TD and 5 healthy normal controls (NCs), destined for transcriptome sequencing. After thorough preprocessing of the RNA sequencing data, a differential expression analysis was performed to identify genes that significantly differentiated the TD group from the NCs. To identify candidate genes, an intersection analysis was performed between the differentially expressed genes (DEGs) and the key module genes obtained through weighted gene co-expression network analysis. The candidate genes underwent Mendelian randomization (MR) analysis and least absolute shrinkage and selection operator analysis to identify key genes. We conducted experimental validation and sensitivity analyses, such as pleiotropy, heterogeneity, and leave-one-out evaluations, to ensure the robustness of our findings. RESULTS: The findings present new evidence indicating that SLC8A1 facilitates the progression of TD. MR analysis established a causal link between SLC8A1 and TD progression (p < 0.05). The study indicated that SLC8A1 might inhibit TD progression by negatively regulating gamma-glutamylisoleucine levels. In SD rats, TD led to a disordered arrangement of collagen structures, increased infiltration of inflammatory cells, increased cell density, and thicker inflammatory hyperplasia in tendon. These results confirm the effective creation of a TD model. Analysis showed significant upregulation of SLC8A1 expression in the TD group (p < 0.05). CONCLUSION: This research highlights SLC8A1 as a potential biomarker in TD development, providing novel perspectives for clinical diagnosis and treatment strategies.