β-Thujaplicin Mobilizes Renal Tubular Iron to Alleviate Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus. Iron metabolism is implicated in the pathogenesis of DKD; however, its mechanistic basis and therapeutic implications remain incompletely explored. Here, we employed unilateral nephrectomy combined with streptozotocin-induced DKD mice to identify distinct renal iron metabolic profiles in DKD versus controls. Notably, although total renal iron content remained unchanged, pronounced iron deposition was detected in proximal renal tubules of DKD mice compared with controls. This aberrant iron deposition correlated with elevated fibrotic markers, indicating a potential mechanistic link between iron dysregulation and renal fibrosis in DKD. Importantly, the iron ionophore β-Thujaplicin (hinokitiol) effectively mobilized tubular iron and significantly attenuated renal fibrosis. Transcriptome analysis revealed that TGF-β signaling, a key fibrotic pathway, was inhibited by β-Thujaplicin. To further elucidate the mechanism of β-Thujaplicin mitigating renal fibrosis, HK-2 cells were exposed to a combination of high glucose, palmitate, and TGF-β1. The results demonstrated that THU alleviated fibrosis in HK-2 cells by reducing oxidative stress, decreasing intracellular iron levels, and inhibiting the TGF-β signaling pathway. Collectively, our findings establish that iron metabolic reprogramming drives DKD progression, and pharmacological targeting of tubular iron deposition via iron ionophores represents a promising strategy against renal fibrosis in DKD and related nephropathies.