Lipidomic profiling reveals medium-chain acylcarnitines alterations as metabolic signatures in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN), the most common primary glomerulonephritis worldwide, exhibits highly variable clinical progression, ranging from asymptomatic urinary abnormalities with potential for spontaneous resolution to progressive kidney failure over 10–20 years. The limited understanding of IgAN pathogenesis continues to constrain the development of effective therapeutic strategies. To elucidate key pathogenic mechanisms, we performed both untargeted and quantitative lipidomic profiling in patients with IgAN. Our results revealed significant disruptions in carnitine metabolism, particularly involving medium-chain acylcarnitines. Notably, medium-chain acylcarnitine levels were strongly correlated with clinical markers of renal function, including serum creatinine and estimated glomerular filtration rate (eGFR). Given their role as key intermediates in mitochondrial fatty acid β-oxidation, we further investigated mitochondrial function. Analysis of transcriptomic data (GSE210098) showed that genes related to the mitochondrial respiratory electron transport chain and oxidative phosphorylation (OXPHOS) system were significantly downregulated in IgAN progressors. Moreover, OXPHOS activity was markedly impaired in renal tubular epithelial cells from IgAN patients (GSE171314). These findings implicate dysregulated medium-chain acylcarnitine metabolism as a potential contributor to IgAN pathogenesis. Importantly, our data suggest a protective role for carnitine in disease development, highlighting a potential novel therapeutic avenue for IgAN.