Deficiency of thiosulfate sulfurtransferase mediates the dysfunction of renal tubular mitochondrial fatty acid oxidation in diabetic kidney disease.

One of the main characteristics of diabetic kidney disease (DKD) is abnormal renal tubular fatty acid metabolism, especially defective fatty acid oxidation (FAO), accelerating tubular injury and tubulointerstitial fibrosis. Thiosulfate sulfurtransferase (TST), a mitochondrial enzyme essential for sulfur transfer, is reduced in metabolic diseases like diabetes and obesity. However, the potential role of TST in regulating fatty acid metabolic abnormalities in DKD remains unclear. Here, our data revealed decreased TST expression in the renal cortex of DKD patients. TST deficiency exacerbated tubular impairment in both diabetic and renal fibrosis mouse models, while sodium thiosulfate treatment or TST overexpression mitigated renal tubular injury with high-glucose exposure. TST downregulation mediated the decrease in S-sulfhydration of very long-chain specific acyl-CoA dehydrogenase, resulting in mitochondrial FAO dysfunction. This sequence of events exacerbates the progression of tubulointerstitial injury in DKD. Together, our findings demonstrate TST as a regulator of renal tubular injury in DKD.