Baicalein Alleviates Iron Overload-Induced Ferroptosis and Osteogenic Blockade in Osteoblasts by Activating the Nrf2/GPX4 Pathway

TL;DR

Baicalein, a natural compound, protects bone cells from iron overload damage by reducing cell death and promoting bone health through a specific pathway.

Contribution

This is the first study to show baicalein's dual action in iron chelation and antioxidation to prevent bone loss from iron overload.

Findings

Baicalein chelates iron and reduces oxidative stress in osteoblasts under iron overload.

It activates the Nrf2/GPX4 pathway, which suppresses ferroptosis and restores osteogenic differentiation.

In mice, baicalein reduces iron deposition and bone loss, effects blocked by Nrf2 inhibition.

Abstract

Objective: This study aimed to investigate the protective effects and underlying mechanisms of baicalein against iron overload-induced osteoblast dysfunction and bone loss. Impact Statement: This research is the first to demonstrate that baicalein, a natural flavonoid, functions as a dual-action agent combining iron chelation and antioxidation to prevent iron overload-induced ferroptosis in osteoblasts, offering a novel therapeutic strategy for iron overload-related osteoporosis. Introduction: Iron overload contributes to osteoblast damage and osteoporosis through ferroptosis, an iron-dependent cell death pathway. Current treatments fail to simultaneously address iron accumulation and bone loss, highlighting the need for effective dual-function therapies. Methods: Using iron dextran-treated MC3T3-E1 osteoblasts and a murine iron overload model, we assessed the effects of baicalein on cell viability, osteogenic differentiation, ferroptosis markers, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) pathway via biochemical assays, Western blot, and micro-computed tomography. Genetic and pharmacological inhibition of Nrf2 were applied to validate the mechanism. Results: Baicalein chelated iron, scavenged reactive oxygen species, and suppressed ferroptosis in osteoblasts, restoring differentiation under iron overload. It activated Nrf2 nuclear translocation and upregulated GPX4/solute carrier family 7-member 11 (SLC7A11) expression. In mice, baicalein reduced iron deposition, oxidative stress, and bone loss, and these effects were abolished by Nrf2 inhibition. Conclusion: Baicalein alleviates iron overload-induced osteoblast ferroptosis and osteoporosis by activating the Nrf2/GPX4 pathway, supporting its clinical potential as a therapeutic agent for iron-related bone disorders.

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