Homo sapiens Genome sequencing and assembly

Osteoarthritis (OA) progression is closely related to dysregulated glycolysis. As the primary metabolite of glycolysis, lactate plays a detrimental role in OA. However, how lactate exacerbates OA remains unclear. Here, single-cell transcriptomic analysis revealed an overall increase in the expression of glycolysis related genes in OA joints. Increased lactate production and pan-lactylation level were observed in OA chondrocytes. Also, the detrimental effects of hyper-lactylation in OA had been proven in this study. We further identified that lysine 6th (K6) lactylation of UDP-glucose dehydrogenase (UGDH) weakened the protective effects of UGDH by repressing its enzymatic activity and regulating its nuclear and cytoplasmic distribution. Moreover, A485-induced specific inhibition of acyltransferase p300, which is the writer of UGDH lactylation, significantly decreased the lactylation level of UGDH and relieved OA in vivo and in vitro. Mechanistically, K6 lactylation of UGDH impeded the interaction between UGDH and signal transducers and activators of transcription 1 (STAT1) in nucleus, leading to upregulated transcription of Mitogen-Activated Protein Kinase Kinase Kinase 8 (MAP3K8) and activated MAPK pathway. Our findings reveal that P300-catalyzed lactylation of UGDH promotes OA progression and provide a potential therapeutic target for OA treatment.