SLC16A9-mediated uric acid uptake promotes myocardial hypertrophy in dilated cardiomyopathy via NLRP3 inflammasome activation

Background Dilated cardiomyopathy (DCM) is a leading cause of heart failure with limited therapeutic options. Elevated uric acid (UA) levels serve as an independent risk factor for cardiovascular diseases, yet the specific mechanisms mediating cardiomyocyte UA uptake remain elusive. This study aimed to identify novel targets that regulate myocardial UA transport and to elucidate their role in the progression of DCM. Methods Differentially expressed genes were identified from four GEO transcriptome datasets (GSE3586, GSE79962, GSE84796, and GSE120895). The functional role of solute carrier family 16 member 9 (SLC16A9) was validated in doxorubicin-induced DCM mice and in H9c2 cells treated with exogenous UA. SLC16A9 was silenced using shRNA in vitro and AAV9-mediated gene delivery in vivo. UA concentrations, NLRP3 inflammasome activation, and myocardial hypertrophy were assessed. Paracrine effects were evaluated using co-culture systems. Results SLC16A9 was identified as a consistently upregulated transporter across all four datasets. Myocardial SLC16A9 expression was positively correlated with tissue UA levels. SLC16A9 silencing attenuated intracellular UA accumulation without affecting xanthine oxidase activity in UA-treated cardiomyocytes. Mechanistically, UA uptake activated the NLRP3 inflammasome pathway, promoting cardiomyocyte hypertrophy and transforming growth factor β1 (TGF-β1)-mediated fibroblast activation via paracrine signaling. Therapeutic SLC16A9 silencing in vivo significantly reduced myocardial hypertrophy and interstitial fibrosis, with combined SLC16A9 silencing and allopurinol treatment providing additive benefits. Conclusion SLC16A9 serves as a critical mediator of UA uptake in the DCM myocardium. Silencing SLC16A9 reduces intracellular UA accumulation, thereby suppressing the NLRP3-TGF-β1 signaling cascade and effectively alleviating myocardial hypertrophy. These findings provide a new molecular target for the precise treatment of DCM.