Identification of Thioredoxin-Interacting Protein as an Upstream Regulator of Ferroptosis in Hyperuricemic...

Hyperuricemic nephropathy (HN) is a major contributor to chronic kidney disease, yet current urate-lowering therapies often fail to halt tubular injury once established. While ferroptosis is known to drive renal injury in HN, the upstream molecular mechanisms remain unclear. We investigated whether thioredoxin-interacting protein (TXNIP) acts as an upstream regulator linking hyperuricemia to ferroptosis-associated tubular injury in HN.

TXNIP expression was examined in renal biopsies from patients with HN and two murine models (drug-induced and Uox^-/- mice). Functional studies combined pharmacological suppression of TXNIP expression using verapamil with genetic validation in a novel Uox^-/-Txnip^-/- double-knockout model. Renal injury and ferroptosis-associated alterations were assessed using biochemical, molecular, histological, ultrastructural, and transcriptomic analyses.

TXNIP was markedly upregulated and predominantly localized to renal tubular epithelial cells in both murine models and patients with HN. Verapamil-associated suppression of TXNIP expression attenuated renal dysfunction, tubular injury, inflammation, and interstitial fibrosis without significantly reducing serum urate. The novel Uox^-/-Txnip^-/- model provided direct genetic evidence that TXNIP contributes to the hyperuricemic renal phenotype. Across the pharmacological and genetic approaches, renal protection was accompanied by reduced tubular iron accumulation and lipid peroxidation, restoration of glutathione (GSH) content and xCT/GPX4 expression, decreased ACSL4 expression, and attenuation of ferroptosis-associated mitochondrial abnormalities.

These findings identify TXNIP as an upstream regulator of ferroptosis-associated tubular injury in HN and provide genetic evidence for its contribution to the hyperuricemic renal phenotype. The pharmacological findings further suggest that targeting TXNIP-associated injury pathways may complement conventional urate-lowering therapy. Antioxid. Redox Signal. 00, 000-000.