<p>Osteoarthritis (OA) is a chronic, disabling condition whose pathogenesis remains unclear. TRPM4 is closely associated with OA, but its specific roles and regulatory networks within different cell subsets remain to be elucidated. This study integrates single-cell and transcriptomic sequencing data to systematically analyse the cell-specific expression patterns, key downstream molecules, and regulatory networks of TRPM4, with the aim of identifying new therapeutic targets for OA. OA-related datasets were obtained from public databases. Key cells were identified at the single-cell level, and analyses including enriched pathways and cell communication were conducted. Candidate genes were screened by cross-referencing differentially expressed genes (DEGs), key module genes from high-dimensional weighted gene co-expression network analysis (hdWGCNA) analysis related to key cells, and TRPM4-related DEGs. We then employed machine learning algorithms and expression levels to screen key genes. Subsequently, analyses such as functional enrichment, immune infiltration analysis, construction of molecular regulatory networks, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were executed. Human Leukocyte Antigen-DR Alpha Chain (HLA-DRA) cells were the key cells, and the enriched pathways they participated in mainly included “FMO oxidizes nucleophiles”, and frequent cell–cell interactions were observed between HLA-DRA cells and synovial subintimal fibroblasts (SSF) in OA. Later, 2 key genes (FOSL2 and S100A11) were obtained. S100A11 was up-regulated, while FOSL2 was down-regulated in the OA group, and RT-qPCR showed consistent results (<i>p</i> &lt; 0.05). In addition, FOSL2 and S100A11 shared 14 enriched pathways, such as the p53 pathway and oxidative phosphorylation, and there were infiltration differences of 8 types of immune cells between OA and control samples (<i>p</i> &lt; 0.05). The miRNA–mRNA network (e.g., has-miR-6134-S100A11) was constructed. This study suggested that TRPM4-associated HLA-DRA⁺ antigen-presenting cells may be associated with osteoarthritis, and, based on transcriptomic correlation analysis and limited qPCR validation, identified S100A11 and FOSL2 as candidate biomarkers associated with TRPM4. These findings provided preliminary, hypothesis-generating clues regarding the cellular heterogeneity and immunometabolic pathways in which TRPM4 may be involved in osteoarthritis; however, its specific role remained to be validated by subsequent functional experiments.</p>