Integrated transcriptomic analysis reveals key regulatory mechanisms of HIPK2 in osteoarthritis and identifies potential therapeutic target drugs.

Osteoarthritis (OA) is a prevalent chronic joint disorder characterized by cartilage degeneration and extracellular matrix (ECM) remodeling. HIPK2 is a serine/threonine kinase involved in transcriptional regulation, cell proliferation, and apoptosis. However, its expression pattern and potential relevance in OA remain incompletely understood. We integrated multiple Bulk RNA-seq datasets and single-cell RNA-seq data to characterize HIPK2 expression in OA and explore its transcriptomic associations. Pathway changes associated with different HIPK2 expression states were analyzed using AUCell and gene set variation analysis. Weighted gene co-expression network analysis and least absolute shrinkage and selection operator regression were applied to identify candidate genes associated with HIPK2 and ECM-receptor interaction pathway activity. Molecular docking was further used as an exploratory in silico approach to screen candidate compounds with potential binding affinity to HIPK2. HIPK2 expression was significantly elevated in OA and was mainly associated with fibrocartilage chondrocytes across both Bulk RNA-seq and single-cell transcriptomic sequencing analyses. Higher HIPK2 expression was accompanied by lower activity of several ECM-related pathways, especially the ECM-receptor interaction pathway. Weighted gene co-expression network analysis and least absolute shrinkage and selection operator analyses identified ZNF638, DMXL1, and VEZT as candidate genes associated with both HIPK2 expression and ECM-receptor interaction pathway activity. In addition, molecular docking suggested 6 compounds with potential binding affinity to HIPK2, including progesterone, estradiol, ethinyl estradiol, coumestrol, biotin, and phenobarbital. Our integrative transcriptomic analyses suggest that HIPK2 is associated with OA and may be involved in ECM-related dysregulation in fibrocartilage chondrocytes. ZNF638, DMXL1, and VEZT may represent candidate genes linked to this process. The docking results provide preliminary candidate compounds for future validation. Overall, these findings are hypothesis-generating and require further experimental confirmation in vitro and in vivo.