School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, China.
Department of Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang 310007, China.
Phytomedicine. 2024 Feb;124:155282. doi: 10.1016/j.phymed.2023.155282. Epub 2023 Dec 14.
Ferroptosis is a crucial contributor to impaired osteoblast function in osteoporosis. Mangiferin, a xanthonoid glucoside isolated from mangoes, exhibits anti-osteoporosis effects. However, its potential mechanism is not fully understood.
This study explores the potencies of mangiferin on osteoblastic ferroptosis and deciphers its direct target in the context of solute carrier family 7-member 11 (SLC7A11)/glutathione peroxidases 4 (GPX4) pathway.
In vivo models include bilateral ovariectomy induced osteoporosis mice, iron-dextran induced iron-overloaded mice, and nuclear factor-erythroid 2-related factor 2 (Nrf2)-knockout mice. Mice are orally administrated mangiferin (10, 50 or 100 mg.kgd) for 12 weeks. In vitro osteoblast models include iron-dextran induced iron-overloaded cells, erastin induced ferroptosis cells, and gene knockout cells. RNA sequencing is applied for investigating the underlying mechanisms. The direct target of mangiferin is studied using a cellular thermal shift assay, silico docking, and surface plasmon resonance.
Mangiferin promotes bone formation and inhibits ferroptosis in vivo models (osteoporosis mice, iron-overloaded mice) and in vitro models (ferroptosis osteoblast, iron-overloaded osteoblasts). Mechanismly, mangiferin directly binds to the kelch-like ECH-associated protein 1 (Keap1) and activates the downstream Nrf2/SLC7A11/GPX4 pathway in both the in vivo and in vitro models. Mangiferin failed to restore the osteoporosis and ferroptosis in Nrf2-knockout mice. Silencing Nrf2, SLC7A11 or GPX4 abolished the anti-ferroptosis effect of mangiferin in erastin-induced cells. Addition of the ferroptosis agonist RSL-3 also blocked the protective effects of mangiferin on iron-overloaded cells. Furthermore, mangiferin had better effects on osteogenesis than the ferroptosis inhibitor (ferrostatin-1) and the Nrf2 agonists (sulforaphane, dimethyl fumarate, and bardoxolone).
We identify for the first time mangiferin as a ferroptosis inhibitor and a direct Keap1 conjugator that promotes bone formation and alleviates osteoporosis. This work also provides a potentially practical pharmacological approach for treating ferroptosis-driven diseases.
铁死亡是骨质疏松症中破骨细胞功能受损的关键因素。芒果中的一种黄烷酮糖苷芒果苷具有抗骨质疏松作用。然而，其潜在机制尚不完全清楚。
本研究探讨了芒果苷对成骨细胞铁死亡的作用，并在溶质载体家族 7 成员 11（SLC7A11）/谷胱甘肽过氧化物酶 4（GPX4）途径中解析其直接靶标。
体内模型包括双侧卵巢切除诱导的骨质疏松症小鼠、铁右旋糖苷诱导的铁过载小鼠和核因子-红细胞 2 相关因子 2（Nrf2）-敲除小鼠。小鼠口服给予芒果苷（10、50 或 100mg/kg/d）12 周。体外成骨细胞模型包括铁右旋糖苷诱导的铁过载细胞、依马替尼诱导的铁死亡细胞和基因敲除细胞。应用 RNA 测序研究潜在机制。利用细胞热转移分析、计算机对接和表面等离子体共振研究芒果苷的直接靶标。
芒果苷在体内（骨质疏松症小鼠、铁过载小鼠）和体外模型（铁死亡成骨细胞、铁过载成骨细胞）中促进骨形成并抑制铁死亡。机制上，芒果苷直接与 Kelch-like ECH-associated protein 1（Keap1）结合，在体内和体外模型中激活下游 Nrf2/SLC7A11/GPX4 途径。芒果苷未能恢复 Nrf2 敲除小鼠的骨质疏松症和铁死亡。沉默 Nrf2、SLC7A11 或 GPX4 消除了芒果苷在依马替尼诱导的细胞中抗铁死亡的作用。添加铁死亡激动剂 RSL-3 也阻断了芒果苷对铁过载细胞的保护作用。此外，与铁死亡抑制剂（ferrostatin-1）和 Nrf2 激动剂（萝卜硫素、富马酸二甲酯和 bardoxolone）相比，芒果苷对成骨作用的效果更好。
我们首次发现芒果苷是一种铁死亡抑制剂和直接的 Keap1 缀合物，可促进骨形成并缓解骨质疏松症。这项工作还为治疗铁死亡驱动的疾病提供了一种潜在的实用药理学方法。
