Diosmin attenuates UUO-induced renal ferroptosis and fibrosis by inhibiting the HIF-1α/FABP4 signaling axis

Background and purpose: Renal fibrosis is a major pathological feature of chronic kidney disease (CKD) that poses significant therapeutic challenges owing to its irreversible nature. In this study, we aimed to investigate the effects of diosmin, a polyphenolic flavonoid with anti-inflammatory, antioxidant, and antifibrotic properties, on renal fibrosis and to explore the underlying mechanisms.

Study design and methods: Mouse renal fibrosis model induced by UUO surgery and an HK-2 cell fibrosis model stimulated by TGF-β1 were established to evaluate the effects of diosmin treatment on cell injury, inflammatory response, and Ferroptosis. Changes in the expression of related genes in the kidney tissues were analyzed using RNA-seq. In addition, the effects of fatty acid-binding protein 4 (FABP4) on the efficacy of diosmin were explored by knockdown and overexpression of FABP4. Double luciferase reporter gene assay, Chip-qPCR, molecular docking, surface plasmon resonance, and cellular thermal shift experiments were performed to explore this mechanism.

Results: Diosmin mitigated renal tubular injury and Collagen deposition in the UUO model by modulating fibrotic markers, such as fibronectin, Col I α1, and α-SMA. It also reduces iron accumulation, decreases the expression of MDA, ASCL4, and inflammatory cytokines, and increases the expression of GPX4 and SOD2, thereby attenuating Ferroptosis and enhancing the cellular response to oxidative stress. In vitro, diosmin counteracted TGF-β1-induced cellular damage and Ferroptosis. RNA-seq analysis revealed that diosmin intervention suppressed the expression of FABP4 induced by UUO and targeted silencing of FABP4 attenuated cellular damage and Ferroptosis. Conversely, FABP4 overexpression in vivo compromised the renoprotective effects of diosmin. Mechanically, diosmin was found to bind to HIF-1α and reduce its nuclear translocation, thereby inhibiting FABP4 transcription, resulting in reduced inflammation, Collagen deposition, and Ferroptosis. Furthermore, the overexpression of HIF-1α reversed the protective effects of diosmin.

Conclusion: Diosmin potentially attenuates renal Ferroptosis and fibrosis through the inhibition of the HIF-1α/FABP4 axis, offering a promising therapeutic approach for renal fibrosis.

Diosmin; FABP4; Ferroptosis; HIF-1α; Renal interstitial fibrosis.