Pathogenic Implications of the THY1/NF-κB Feedback Relationship in Osteoarthritis and Its Potential as a Therapeutic Target

Yiqun Yan,1,2 Chen Wang,1,2 Mingjun Zhang,1,2 Entong Ji,1,2 Jiangqi Yu,3 Wendan Cheng1,2 1Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People’s Republic of China; 2Institute of Orthopaedics, Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People’s Republic of China; 3Department of Information, the 970th Hospital of Joint Logistics Support Force, Weihai, Shandong Province, 264200, People’s Republic of ChinaCorrespondence: Wendan Cheng, Email [email protected]; [email protected] Jiangqi Yu, Email [email protected]: Osteoarthritis (OA) is a chronic inflammatory disease primarily characterized by cartilage damage, and its pathological mechanisms remain to be elucidated.Objective: This study aimed to identify potential therapeutic targets for OA and to further explore their associated molecular mechanisms.Methods: Candidate OA-associated genes were identified by integrating differential expression analysis, WGCNA, and PPI network analysis. Diagnostic marker genes were subsequently determined using machine-learning algorithms (RF, LASSO, and SVM-RFE) and further validated by ROC analysis and nomogram modeling. Single-cell sequencing analyses were conducted to characterize the temporal dynamics of these marker genes across the developmental trajectory of OA chondrocytes. Both in vitro and in vivo experiments were performed to confirm the expression of key molecules and the activation of relevant pathways. In addition, berberine, a natural isoquinoline alkaloid with anti-inflammatory potential, was selected as a candidate compound to evaluate its interaction with THY1 by molecular docking and molecular dynamics simulation.Results: A total of 19 candidate OA-associated hub genes were identified. By integrating three machine-learning algorithms, THY1 was determined as a diagnostic marker gene for OA, and ROC curves and a nomogram model confirmed its favorable diagnostic/predictive performance. Single-cell sequencing further suggested a gradual upregulation of THY1 during chondrocyte development in OA. Both in vitro and in vivo experiments supported the feasibility of THY1 as a potential therapeutic target. Computational simulations demonstrated favorable binding between berberine and THY1.Conclusion: This study suggests that THY1 may serve as a diagnostic biomarker for OA and may be involved in disease progression through its association with the NF-κB signaling pathway. Moreover, our computational simulations provide preliminary and predictive structural insights into the potential interaction between berberine and THY1, thereby expanding possible research directions for berberine-based approaches in OA.Keywords: osteoarthritis, THY1, NF-κB signaling, berberine