Work

Iron overload disrupts bone homeostasis via dual pathways: inducing ferroptosis of preosteoblastic cells and shaping a proinflammatory immune milieu

Year: 2026

Type: article

Abstract: Iron overload is regarded as an independent risk factor for osteoporosis, yet the underlying molecular mechanisms remain incompletely understood. In this study, we systematically investigated the impact of iron overload on bone homeostasis using a combination of in vivo and in vitro models. An iron overload rat model was established, and investigations were complemented by cellular assays utilizing mouse embryonic osteoblast precursor cells (MC3T3-E1) and macrophages. The in vivo results demonstrated that iron overload significantly reduced bone mineral density (BMD) and disrupted bone microarchitecture. These structural changes were accompanied by an enhanced inflammatory response within the bone tissue and the aberrant expression of ferroptosis markers. The in vitro experiments confirmed that iron overload induced ferroptosis and inhibited osteogenic differentiation in MC3T3-E1 cells by triggering oxidative stress, lipid peroxidation, and mitochondrial damage. This process was closely associated with the significant upregulation of the ATPase H+ transporting V0 subunit D2 ( Atp6v0d2 ) gene. Notably, plasmid-mediated knockdown of Atp6v0d2 substantially alleviated ferroptosis and rescued osteogenic function in iron-overloaded preosteoblastic cells. Furthermore, our study revealed that iron overload drove macrophages toward a pro-inflammatory M1 phenotype. Conditioned medium from these polarized M1 macrophages induced apoptosis and cell cycle arrest in preosteoblastic cells while promoting osteoclast differentiation, an effect mediated by the activation of the IL-17 signaling pathway. In conclusion, this study revealed a dual mechanism by which iron overload disrupted bone homeostasis: it directly induced ferroptosis in osteogenic cells and indirectly shaped a pro-inflammatory immune microenvironment. These findings provide novel insights into the pathogenesis of iron overload-induced osteoporosis and offer a new perspective for understanding bone metabolic dysregulation under iron overload conditions.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1905654

Authors: Yu Pan, Renfeng Zhao, Chengdong Zhang, Feng Shi, Hui Wu, Dongqin Xiao

Institutions: North Sichuan Medical University, Capital Medical University, Nanchong Central Hospital, China West Normal University

Language: English

Topic: Bone Metabolism and Diseases

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,801