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Mangiferin attenuates osteoporosis by inhibiting osteoblastic ferroptosis through Keap1/Nrf2/SLC7A11/GPX4 pathway
Xuehui Deng1, Bingfeng Lin2, Fang Wang1
1School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, China.
Background:
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.
Purpose:
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.
Methods:
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.kg-1.d-1) 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.
Results:
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).
Conclusions:
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.
Insights
Mangiferin inhibits osteoblast ferroptosis by directly targeting Keap1, activating the Nrf2/SLC7A11/GPX4 pathway. This natural compound promotes bone formation and alleviates osteoporosis, offering a new therapeutic strategy.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Ferroptosis significantly impairs osteoblast function and contributes to osteoporosis.
- Mangiferin, a mango-derived compound, shows anti-osteoporosis potential, but its mechanism remains unclear.
- Understanding mangiferin's role in osteoblastic ferroptosis is crucial for developing new osteoporosis treatments.
Purpose of the Study:
- To investigate mangiferin's effects on osteoblastic ferroptosis.
- To identify mangiferin's direct molecular target within the solute carrier family 7-member 11 (SLC7A11)/glutathione peroxidases 4 (GPX4) pathway.
Main Methods:
- In vivo studies utilized osteoporosis and iron-overloaded mouse models, with mangiferin administered orally.
- In vitro models included iron-overloaded and erastin-induced ferroptosis osteoblast cells, alongside gene knockout studies.
- Mechanism exploration involved RNA sequencing, cellular thermal shift assay, in silico docking, and surface plasmon resonance to identify mangiferin's direct target.
Main Results:
- Mangiferin demonstrated bone formation promotion and ferroptosis inhibition in both in vivo and in vitro models.
- Mangiferin directly binds to kelch-like ECH-associated protein 1 (Keap1), activating the Nrf2/SLC7A11/GPX4 pathway.
- The protective effects of mangiferin were dependent on Nrf2, SLC7A11, and GPX4, and it outperformed known ferroptosis inhibitors and Nrf2 agonists.
Conclusions:
- Mangiferin is identified as a novel ferroptosis inhibitor and a direct Keap1 conjugator.
- Mangiferin promotes bone formation and alleviates osteoporosis by targeting the Keap1-Nrf2 pathway.
- This research presents mangiferin as a promising therapeutic agent for ferroptosis-driven diseases like osteoporosis.
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