KRT20 suppresses the exosomal secretion of PRDX2 to mitigate ferroptosis in acute kidney injury

Acute kidney injury (AKI) is a commonly observed but poorly understood clinical syndrome. Keratin 20 (KRT20), a key component of intermediate filaments, is generally known as a biomarker of renal tubular injury, but its role in kidney disease remains unclear. By bioinformatics analysis and further laboratory validation, we confirmed that expression of KRT20 was highly upregulated in the renal proximal tubular cells (RPTC) during the early phase of AKI prior to the rise of KIM1 gene expression. We reported here that KRT20 was upregulated via Fosb in the kidneys of ischemia/reperfusion injury and cisplatin-nephrotoxic AKI mice. Knockout of KRT20 specifically in RPTC aggravated AKI. Mechanistically, KRT20 protected against AKI by sequestering peroxiredoxin 2 (PRDX2), an antioxidant protein, to prevent renal tubular cell ferroptosis. Specifically, KRT20 bound to PRDX2 to suppress its exosomal secretion from kidney tubular cells. We further found that ALG-2-interacting protein X (Alix) interacts with PRDX2 to mediate its exosomal secretion and KRT20 competed with Alix to interact with PRDX2 at its N terminal domain and thereby inhibiting its exosomal secretion. Finally, we showed that the expression of KRT20 and PRDX2 correlated with kidney injury and decline of renal function in AKI patients. In conclusion, KRT20 is upregulated in early AKI to protect kidney tubule cells by sequestering PRDX2 and inhibiting ferroptosis. KRT20 could be an early biomarker for AKI and a potential drug target for AKI prevention and therapy.