Targeting SAT1 alleviates high glucose-induced tubular ferroptosis and fibrosis: implications for diabetic kidney disease.

Abstract

Renal tubular damage and interstitial fibrosis are highly linked to diabetic kidney disease (DKD) progression. Ferroptosis in renal tubular epithelial cells has emerged as one of the key mechanisms of DKD. Spermidine/spermine N1-acetyltransferase 1 (SAT1) knockdown has been found to alleviate repetitive low-dose cisplatin-induced kidney damage and fibrosis, and importantly, SAT1 silencing represses cellular sensitivity to ferroptosis. However, the effect of SAT1 on DKD-associated ferroptosis and its potential mechanism remain understood. In this study, we constructed a high-fat diet/streptozotocin-induced DKD mouse model and a high glucose (HG)-injured HK-2 cell model with the aim of verifying whether SAT1 silencing attenuates DKD tubular damage by regulating ferroptosis. We found that SAT1 was upregulated in DKD mouse kidneys and HG-treated HK-2 cells. Significant tubular damage, fibrosis, ferroptosis, and oxidative stress were observed in DKD mouse kidneys. In an in vitro loss-of-function assay, SAT1 silencing suppressed HG-induced HK-2 cytotoxicity, extracellular matrix (ECM) synthesis, and inflammation. Additionally, SAT1 silencing decreased HG-activated MDA and 4-HNE production, while restoring GSH levels. SAT1 silencing also abrogated HG-activated ferroptosis in HK-2 cells, as evidenced by a reduction in iron overload, inhibition of lipid peroxidation, and upregulation of ferroptosis-related protein (SLC7A11, GPX4, and TFR1) expression. Mechanistically, SAT1 silencing facilitated nuclear translocation and expression of NRF2. Impairment of NRF2 function abrogated the inhibitory effects of SAT1 silencing on HG-stimulated HK-2 cytotoxicity, ferroptosis, and ECM accumulation. Overall, the SAT1/NRF2 axis is a critical regulator of tubular damage in DKD, and suppression of SAT1 may be an underlying target for DKD treatment.

Key Findings

• SAT1 is upregulated in diabetic kidney disease (DKD) mouse kidneys and high glucose-treated HK-2 cells.
• Silencing SAT1 reduces tubular damage, fibrosis, ferroptosis, oxidative stress, and inflammation in DKD models.
• SAT1 silencing promotes NRF2 nuclear translocation and expression, which is essential for its protective effects against ferroptosis and extracellular matrix accumulation.

Clinical Significance

Citation

Tang Yingqi, Wang Siyao, Wang Yuet al.. Targeting SAT1 alleviates high glucose-induced tubular ferroptosis and fibrosis: implications for diabetic kidney disease. Histochemistry and cell biology. 2026-Apr-05.