Zhou Yi, Hu Tianchi, Zeng Huarong, Lin Lin, Xie Huan, Lin Rong, Huang Mengya
Department of Endocrinology, Xiamen Hospital, Beijing University of Chinese Medicine/Xiamen TCM Hospital Affiliated to Fujian University of Traditional Chinese Medicine/Xiamen Hospital of Traditional Chinese Medicine, Xiamen City, People's Republic of China.
Graduate School, Fujian University of Traditional Chinese Medicine, Fuzhou City, People's Republic of China.
Drug Dev Res. 2025 Feb;86(1):e70044. doi: 10.1002/ddr.70044.
Naringenin has the potential to regulate ferroptosis and mitigate renal damage in diabetic nephropathy (DN). However, it remains unclear whether the naringenin's effects in DN are linked to its ability to regulate ferroptosis. This study investigated the potential anti-ferroptosis properties of naringenin in high glucose (HG)-induced renal tubular epithelial cell models. HK-2 cells were cultured in HG medium to establish the DN cell model. HK-2 cells were treated with different doses of naringenin to explore the effect of naringenin. The CCK-8 results show that 50 μM ~ 200 μM of naringenin do not affect the viability of HK-2 cells and the viability of HG-induced HK-2 cells increase in a dose-dependent manner with naringenin treatment. Additionally, naringenin increased the levels of IL-10 while decreasing the levels of IL-1β, TNF-α, IL-6, and ROS in HG-induced HK-2 cells. Naringenin also reduced the levels of Fe, oxidized lipid ROS, MDA, 4-HNE, ACSL4, and TFR1 in HG-induced HK-2 cells, while increasing the levels of non-oxidized lipid ROS, SOD, GSH-Px, SLC7A11, and GPX4. Meanwhile, naringenin restored the levels of MMP, ATP and MPTP opening, reduced OCR in HG-induced HK-2 cells. Furthermore, naringenin reversed the decreased expression of SIRT1, p-FOXO3a, Nrf2 and Nuclear Nrf2 caused by HG. SIRT1 inhibitor EX527 and Nrf2 inhibitor ML385 attenuated the effects of naringenin on ferroptosis in HG-induced HK-2 cells, with EX527 demonstrating a stronger reversal effect on ferroptosis than ML385. These results suggest that naringenin inhibits ferroptosis in HG-induced HK-2 cells mainly through SIRT1/FOXO3a signaling pathway. This finding further enhanced our understanding of the mechanism behind naringenin's protective effect on DN.
柚皮素具有调节铁死亡和减轻糖尿病肾病（DN）肾损伤的潜力。然而，柚皮素在DN中的作用是否与其调节铁死亡的能力有关仍不清楚。本研究在高糖（HG）诱导的肾小管上皮细胞模型中研究了柚皮素潜在的抗铁死亡特性。将HK-2细胞培养于HG培养基中以建立DN细胞模型。用不同剂量的柚皮素处理HK-2细胞以探究柚皮素的作用。CCK-8结果显示，50μM至200μM的柚皮素不影响HK-2细胞的活力，且随着柚皮素处理，HG诱导的HK-2细胞活力呈剂量依赖性增加。此外，柚皮素增加了HG诱导的HK-2细胞中IL-10的水平，同时降低了IL-1β、TNF-α、IL-6和ROS的水平。柚皮素还降低了HG诱导的HK-2细胞中Fe、氧化脂质ROS、MDA、4-HNE、ACSL4和TFR1的水平，同时增加了非氧化脂质ROS、SOD、GSH-Px、SLC7A11和GPX4的水平。同时，柚皮素恢复了HG诱导的HK-2细胞中MMP、ATP水平和MPTP开放，降低了OCR。此外，柚皮素逆转了HG引起的SIRT1、p-FOXO3a、Nrf2和核Nrf2表达降低。SIRT1抑制剂EX527和Nrf2抑制剂ML385减弱了柚皮素对HG诱导的HK-2细胞铁死亡的影响，EX527对铁死亡的逆转作用比ML385更强。这些结果表明，柚皮素主要通过SIRT1/FOXO3a信号通路抑制HG诱导的HK-2细胞中的铁死亡。这一发现进一步加深了我们对柚皮素对DN保护作用背后机制的理解。
