Impaired BCAA Catabolism Drives Peritoneal Fibrosis via BCKA-Mediated Suppression of the Pentose Phosphate Pathway

Peritoneal dialysis (PD) is a life-sustaining therapy for kidney failure, yet its long-term viability is compromised by progressive peritoneal fibrosis in some patients. Currently, reliable treatment options are lacking as the pathogenesis remains poorly understood, with the metabolic underpinnings of fibrotic progression remaining particularly elusive.

Using a physiologically relevant framework comprising human primary mesothelial cells and a PD fluid-exposed mouse model, we performed bidirectional genetic and pharmacological modulation of branched-chain amino acid catabolism. Integrated proteomic and metabolomic analyses were conducted to investigate downstream metabolic consequences.

We identified profound impairment in branched-chain amino acid (BCAA) catabolism, centered on a functional bottleneck at the rate-limiting branched-chain α-ketoacid dehydrogenase complex, as a metabolic hallmark of peritoneal fibrosis. Functional uncoupling of the amino acids from their ketoacid derivatives indicated that branched-chain α-ketoacid (BCKA) burden was more closely linked to the fibrotic phenotype than BCAA abundance alone. Mechanistically, BCKA burden was associated with reduced glucose-6-phosphate dehydrogenase expression and activity, lower NADPH-generating capacity, and increased intracellular oxidant burden.

Together, these findings showed that BCKA burden, rather than BCAA abundance alone, more closely tracked fibrotic responses and was linked to reduced pentose phosphate pathway-associated redox capacity in peritoneal fibrosis.