Background <p>Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage loss,&#xa0;yet its molecular underpinnings remain incompletely defined. This study aimed to investigate the regional expression pattern of receptor-interacting protein kinase 3 (<i>RIPK3</i>) in OA cartilage and its association with histopathological severity.</p> Methods <p>Cartilage samples were collected from OA patients and categorized into normal tissue (NT), junction tissue (JT), and lesioned tissue (LT). RNA sequencing was performed to identify differentially expressed genes (DEGs)&#xa0;between&#xa0;NT and JT. Gene enrichment analysis was conducted to explore functional pathways. Immunofluorescence staining was used to validate RIPK3 protein expression and localization.</p> Results <p>Transcriptomic analysis identified 140 differentially expressed genes (DEGs) between NT and JT, with several genes, including <i>RIPK3</i>, <i>CCL19</i>, and <i>ITLN1</i>, significantly up-regulated in JT. <i>RIPK3</i> expression showed a log₂ Fold Change of 2.17 (<i>p</i> &lt; 0.01) and displayed higher protein abundance in LT (3.66-fold vs NT), concordant with the transcriptomic trend. This increase correlated with more severe histopathological damage (Mankin score: LT 33.0 vs. NT 5.6; OARSI score: LT 15.8 vs. NT 1.6). Functional enrichment analysis associated RIPK3 with necroptosis, immune signaling and extracellular matrix catabolism. Immunofluorescence staining confirmed spatial accumulation of RIPK3 in LT, consistent with transcriptomic data.</p> Conclusions <p>RIPK3 is spatially enriched in degenerative regions of OA cartilage and associates with histopathological damage, suggesting its potential involvement in disease progression. These findings provide new insight into the molecular landscape of OA and support RIPK3 for further evaluation as a biomarker and potential therapeutic target.</p>