Punicic acid alleviates osteoarthritis progression through miR-29a-3p-dependent inhibition of the MAP2K6/p38 MAPK...

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive articular cartilage degradation. Punicic acid (PA), a plant-derived n-3 polyunsaturated fatty acid, has been reported to exert anti-inflammatory and anti-apoptotic effects. However, the molecular mechanisms underlying its effects in OA remain incompletely understood. In this study, bioinformatics analysis was performed to identify apoptosis-related differentially expressed genes (DEGs) and enriched signaling pathways associated with OA. An in vitro OA-like model was established using interleukin-1β (IL-1β)-stimulated SW1353 cells, which were subsequently treated with different concentrations of PA. PA suppressed IL-1β-induced expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), matrix metalloproteinase-3 (MMP-3),matrix metalloproteinase-13 (MMP-13), and A Disintegrin And Metalloproteinase with Thrombospondin Motifs 5 (ADAMTS-5) and attenuated apoptosis by modulating Bcl-2-associated X protein (BAX) and B-cell lymphoma 2 (BCL-2) expression. Notably, target prediction and dual-luciferase reporter assays confirmed that mitogen-activated protein kinase kinase 6 (MAP2K6) is a direct target of microRNA-29a-3p (miR-29a-3p), and PA increased miR-29a-3p expression in the in vitro OA-like model. Furthermore, PA inhibited MAP2K6-mediated activation of the p38 mitogen-activated protein kinase (p38 MAPK) pathway, thereby attenuating downstream inflammatory and apoptotic signaling. These findings suggest that PA exerts chondroprotective effects by modulating the miR-29a-3p/MAP2K6/p38 MAPK signaling axis, highlighting its therapeutic potential and supporting the development of miRNA-based therapeutic strategies for OA.