The Role of Ferroptosis in Osteoporosis and Immune Response

Introduction to Ferroptosis and Its Significance in Osteoporosis

Osteoporosis is a systemic metabolic condition that leads to decreased bone mass and increased susceptibility to fractures, particularly among the aging population. Recent studies have highlighted the significant role of ferroptosis, a form of programmed cell death characterized by iron-dependent lipid peroxidation, in the pathophysiology of osteoporosis. Ferroptosis is distinct from traditional forms of cell death such as apoptosis and necrosis, primarily due to its reliance on the accumulation of intracellular iron and the failure of antioxidant defenses, particularly glutathione peroxidase 4 (GPX4) activity (Xiao et al., 2025).

The interplay between ferroptosis and the immune system is complex, as immune cells also undergo ferroptosis, potentially influencing bone metabolism. Understanding the mechanisms by which ferroptosis affects immune responses can provide new therapeutic strategies for managing osteoporosis.

Mechanisms of Ferroptosis and Its Impact on Bone Cells

The Biochemical Pathways of Ferroptosis

Ferroptosis is induced by various pathways that lead to the accumulation of reactive oxygen species (ROS) and lipid peroxides within cells. Key players in this process include the system Xc−, which facilitates the uptake of cysteine, essential for glutathione synthesis. When system Xc− is inhibited or disrupted, it leads to a decrease in glutathione levels, resulting in heightened sensitivity to oxidative stress and subsequent ferroptosis (Xiao et al., 2025).

The primary biochemical mechanisms involved in ferroptosis include:

• Iron Accumulation: Excessive intracellular iron promotes oxidative stress through the Fenton reaction, generating hydroxyl radicals that initiate lipid peroxidation.
• Glutathione Depletion: A reduction in glutathione levels compromises cellular antioxidant defenses, precipitating ferroptosis.
• Inhibition of GPX4: The enzyme GPX4 plays a critical role in reducing lipid peroxides. Inhibition of GPX4, through various pathways, facilitates the onset of ferroptosis.

Effects on Osteoblasts and Osteoclasts

In the context of osteoporosis, ferroptosis affects both osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells). Research indicates that ferroptosis in osteoblasts leads to decreased bone formation and mineralization, further exacerbating the condition. This occurs due to:

1. Increased Lipid Peroxidation: Ferroptosis results in lipid peroxidation, damaging osteoblast membranes and impairing their function.
2. Alteration of Bone Microenvironment: The death of osteoblasts triggers a cascade of inflammatory responses, promoting the differentiation of osteoclasts and leading to increased bone resorption.

In osteoclasts, ferroptosis can also be induced under oxidative stress conditions, contributing to bone loss and the progression of osteoporosis. The balance between osteoblast and osteoclast activity is crucial for maintaining bone density, and ferroptosis disrupts this equilibrium (Xiao et al., 2025).

The Relationship Between Ferroptosis and Immune System Function

The immune system plays a pivotal role in the regulation of bone metabolism. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are released during chronic inflammation, leading to increased osteoclast activity and decreased osteoblast function. The activation of immune cells significantly influences the processes involved in bone remodeling (Xiao et al., 2025).

Impact on Immune Cells

Research has demonstrated that ferroptosis can affect the survival and function of various immune cells, including T cells, macrophages, and dendritic cells. The mechanisms through which ferroptosis influences immune function include:

• Iron Uptake: Activated immune cells, particularly macrophages, increase their iron uptake to support proliferation and effector functions. Excessive iron accumulation can trigger ferroptosis in these cells, leading to a diminished immune response.
• Cytokine Production: Ferroptosis can alter the production of cytokines by immune cells, impacting the inflammatory milieu and bone metabolism.
• Oxidative Stress: The oxidative stress generated during ferroptosis can further exacerbate inflammation, leading to a vicious cycle that influences bone health.

Therapeutic Strategies Targeting Ferroptosis in Osteoporosis

Given the multifaceted role of ferroptosis in osteoporosis, targeting this form of cell death presents a novel therapeutic avenue. Strategies may include:

• Iron Chelators: Agents such as deferoxamine can reduce intracellular iron levels, potentially preventing ferroptosis in osteoblasts and thus protecting bone density.
• Antioxidants: Compounds that enhance glutathione levels or mimic GPX4 activity could offer protective effects against ferroptosis, thereby supporting osteoblast function and bone formation.
• Modulation of Inflammatory Responses: Targeting the inflammatory pathways that lead to increased osteoclast activity can help restore the balance between bone resorption and formation.

Table: Potential Therapeutic Strategies for Osteoporosis Targeting Ferroptosis

Conclusion: The Potential of Ferroptosis in Osteoporosis Treatment

Ferroptosis represents a critical intersection between bone metabolism and immune function, with significant implications for the pathogenesis of osteoporosis. By understanding the mechanisms of ferroptosis and its impact on bone cells and the immune system, novel therapeutic strategies can be developed to improve outcomes for individuals suffering from osteoporosis.

The exploration of ferroptosis inhibitors, antioxidants, and modulators of immune responses offers exciting new avenues for research and treatment. As the understanding of ferroptosis and its role in bone health deepens, it may pave the way for innovative approaches to manage and prevent osteoporosis effectively.

FAQ

What is ferroptosis?

Ferroptosis is a form of programmed cell death characterized by the accumulation of lipid peroxides and iron-dependent oxidative stress.

How does ferroptosis relate to osteoporosis?

Ferroptosis affects the function of osteoblasts and osteoclasts, leading to an imbalance in bone remodeling and contributing to bone loss associated with osteoporosis.

What are potential therapies targeting ferroptosis for osteoporosis?

Potential therapies include iron chelators, antioxidants that enhance glutathione levels, and modulators of inflammatory responses to restore balance between osteoblast and osteoclast activity.

Are there any risks associated with targeting ferroptosis?

Targeting ferroptosis presents challenges, including the potential for disrupting normal immune function and maintaining bone homeostasis. Careful evaluation and monitoring are required in clinical applications.

References

1. Xiao, W., Wang, Y., Li, G., & Xu, Y. (2025). Ferroptosis-mediated immune responses in osteoporosis. Journal of Orthopaedic Translation, 2214-031X. https://doi.org/10.1016/j.jot.2025.03.011

2. Ruan, B., Dong, J., Wei, F., Huang, Z., Yang, B., & Zhang, L. (2025). Inhibition of APOC1 promotes the transformation of M2 into M1 macrophages via the ferroptosis pathway and enhances anti-PD1 immunotherapy in hepatocellular carcinoma based on single-cell RNA sequencing. Redox Biology, 56, 102463. https://doi.org/10.1016/j.redox.2022.102463

3. Zeng, L., Yang, K., Yu, G., Hao, W., Zhu, X., & Ge, A. (2024). Advances in research on immunocyte iron metabolism, ferroptosis, and their regulatory roles in autoimmune and autoinflammatory diseases. Cell Death & Disease, 15(5), 510. https://doi.org/10.1038/s41419-024-06807-2

4. Liu, P., Wang, W., Li, Z., Li, Y., Yu, X., & Tu, J. (2022). Ferroptosis: a new regulatory mechanism in osteoporosis. Oxidative Medicine and Cellular Longevity, 2022, 2634431

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