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Ferro-aging: a potential driver of degenerative bone and joint diseases
Songlin Liang1, Shang Gao1, Fumin Wang1
1First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
Abstract:
Degenerative bone and joint diseases (DBJDs), including osteoporosis (OP), osteoarthritis (OA), and intervertebral disc degeneration (IVDD), are chronic age-related disorders characterized by progressive destruction of bone and joint tissues and loss of function, posing a heavy global health burden. Emerging evidence indicates that iron dyshomeostasis, chronic lipid peroxidation, and cellular senescence are common pathological features shared by these diseases. The newly discovered concept of ferro-aging-a non-lethal, persistent cellular state driven by sub-lethal lipid peroxidation that leads to cellular dysfunction and a senescence-associated secretory phenotype (SASP)-provides a unified mechanistic framework linking iron metabolism to age-related degeneration. This review systematically summarizes the molecular basis of ferro-aging, with a focus on the central role of ACSL4 in promoting membrane lipid remodeling and sustaining chronic lipid peroxidation. We discuss how ACSL4-associated ferro-aging contributes to the pathogenesis of OP, OA, and IVDD by disrupting local microenvironmental homeostasis, driving metabolic reprogramming, amplifying inflammatory SASP signaling, and impairing the function of key cell types such as osteoblasts (OBs), chondrocytes, and nucleus pulposus cells (NPCs). The differential response to the same ferro-aging program across different tissues determines the distinct clinical phenotypes of these diseases. Finally, we highlight potential intervention strategies targeting the ACSL4-ferro-aging axis and future research directions, offering new insights for the precision treatment of degenerative bone and joint diseases.
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