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The transcription factor Nrf2 orchestrates cellular defenses against redox imbalance and lipid peroxidation, partly through regulating the expression of 2 key gatekeepers of ferroptosis: SLC7A11 and GPX4 [44]. As such, the Keap1/Nrf2 pathway is recognized as a master regulator of ferroptosis in osteoblasts [45]. Under stress conditions, Nrf2 dissociates from the Keap1–Nrf2 complex, translocates into the nucleus, and initiates the transcription of genes containing antioxidant response elements [46]. Previous studies have reported that Nrf2 activation protects osteoblasts from ferroptosis in bone tissue and alleviates osteoporosis [28,47]. Consistently, we observed that under iron overload conditions, baicalein restored nuclear Nrf2 levels and the expression of downstream targets GPX4 and SLC7A11. Both genetic and pharmacological inhibition of Nrf2 abolished the cytoprotective and pro-osteogenic effects of baicalein. These findings suggest that baicalein prevents ferroptosis in osteoblasts via activation of the Nrf2/GPX4 pathway.

Clinically, iron overload conditions, such as transfusion-induced iron overload in thalassemia and hereditary hemochromatosis, are strongly associated with low bone mass and increased fracture risk [48,49]. Current treatment options (e.g., iron chelators, phlebotomy, and anti-resorptive agents) fail to simultaneously address iron overload and bone damage. Baicalein has undergone human safety and pharmacokinetic studies, which indicate no significant side effects even at high doses [50,51]. Our study demonstrates that baicalein not only prevents bone loss by protecting osteoblasts from ferroptosis but also effectively reduces systemic iron storage. Although beyond the scope of this work, baicalein’s known anti-osteoclastogenic effects may synergistically contribute to its overall bone-protective actions in iron overload conditions. These findings suggest that baicalein is a promising therapeutic agent for iron overload-related bone disorders. Although clinical trials are warranted, the dose of baicalein used in our study was extrapolated from clinically tolerated doses in humans, thereby supporting the potential feasibility of its clinical application.

In summary, this study provides the first definitive evidence that baicalein effectively inhibits iron overload-induced ferroptosis in osteoblasts by activating the Nrf2/GPX4 signaling pathway, thereby promoting bone formation and preventing bone loss. Our findings not only elucidate the mechanism by which baicalein functions as a novel ferroptosis inhibitor in bone protection but also highlight its role as a “dual-function” therapeutic strategy—combining iron chelation and anti-bone-loss capacities. Given its favorable safety profile and existing human pharmacokinetic data, our results provide strong preclinical evidence supporting the clinical translation of baicalein for the treatment of iron overload-related bone diseases. Targeting the ferroptosis pathway, particularly via Nrf2/GPX4 activation by baicalein, represents a highly promising novel strategy for preventing and treating iron overload-induced bone loss.