Targeting G6PD to mitigate cartilage inflammation in TMJOA: The NOX4-ROS-MAPK axis as a therapeutic avenue

•Glucose metabolism of condylar cartilage is enhanced during TMJOA.•Knockdown of G6PD can enhance the resistance of condylar chondrocytes to ROS.•G6PD regulates the inflammatory process of condylar chondrocytes through NOX4-ROS-MAPK axis.•G6PD exerts control over NOX4 activity by orchestrating NADPH production and concurrently influencing NOX4 gene expression. Chondrocytes, known for their metabolic adaptability in response to varying stimuli, play a significant role in osteoarthritis (OA) progression. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, has recently been found to upregulate in OA chondrocyte. However, the exact role of G6PD in temporomandibular joint osteoarthritis (TMJOA) and its effect on chondrocyte function remains unclear. In present study, we induced OA-like conditions in the rat temporomandibular joint via occlusal disharmony (OD), noting a marked increase in G6PD expression in the condylar cartilage. Our data show that G6PD knockdown in mandibular condylar chondrocytes (MCCs) reduces the expression of catabolic enzymes (e.g., MMP3, MMP13) and inflammatory cytokines (e.g., IL6) induced by IL-1β. G6PD knockdown also mitigates IL-1β-induced upregulation of ERK, JNK, and p38 phosphorylation and reduces reactive oxygen species (ROS) levels by decreasing the nicotinamide adenine dinucleotide phosphate (NADPH) and NADPH oxidases 4 (NOX4) mRNA expression. In summary, G6PD appears to regulate the inflammatory state of condylar chondrocytes via the NOX-ROS-MAPK axis, highlighting its potential as a therapeutic target for TMJOA.