A new strategy for preventing and treating orthopedic diseases by regulating ferroptosis through signaling pathways

Abstract

BACKGROUND: Experiments have confirmed that ferroptosis is closely associated with a variety of orthopedic diseases. However, the specific mechanisms by which the regulation of ferroptosis leads to orthopedic diseases remain unclear. Current evidence suggests that signaling pathways may be an important approach for regulating the occurrence of ferroptosis. OBJECTIVE: To summarize the relevant signaling pathways involved in the regulation of ferroptosis in orthopedic diseases (osteoarthritis, spinal cord injury, osteoporosis, intervertebral disc degeneration, rheumatoid arthritis, osteosarcoma, steroid-induced osteonecrosis of the femoral head), to describe the key regulators of the ferroptosis pathway in orthopedic diseases through the modulation of the conduction of signaling pathways, and to conduct an in-depth study on the regulatory mechanisms of ferroptosis in orthopedic diseases and provide a theoretical basis for the prevention and treatment of such diseases. METHODS: Databases including PubMed, Elsevier, Web of Science, and CNKI were searched for relevant literatures on ferroptosis and related orthopedic diseases from the establishment of these databases up to February 2025. The search terms were "ferroptosis, osteoarthritis, osteoporosis, spinal cord injury, intervertebral disc degeneration, osteosarcomas, rheumatoid arthritis, steroid-induced osteonecrosis of the femoral head". A total of 138 articles were included for review. RESULTS AND CONCLUSION: (1) Under the regulation of multiple signaling pathways, the accumulation of intracellular iron ions, reactive oxygen species, and other substances can be induced, causing ferroptosis in osteoblasts, chondrocytes, osteosarcoma cells, etc., leading to changes in the microenvironment, thereby promoting or inhibiting the occurrence of related orthopedic diseases. (2) Studies have confirmed that signaling pathway-regulated ferroptosis is of great significance in the pathogenesis of orthopedic diseases. (3) However, the interaction mechanisms among signaling pathways, ferroptosis, and orthopedic diseases are still in the preliminary stage, and further research is needed to provide more strategies for the treatment of orthopedic diseases.

1. Introduction

The skeleton is a solid structure that maintains body movement, protects internal organs, and performs hematopoietic functions [1]. Orthopedic diseases can be broadly divided into acute traumatic conditions such as fractures and ligament injuries, which can be clinically cured through surgical treatment, and more complex chronic conditions including osteoarthritis [2], rheumatoid arthritis [3-4], and spinal cord injury [5]. These chronic diseases share a common feature: due to the complexity of their pathogenesis, current treatments such as medication and physical therapy can only alleviate their progression, making clinical cure difficult.

As multicellular organisms, humans maintain stability through cells, and whether cells undergo normal programmed cell death (an active and orderly process of cell death [6]) may determine the occurrence of many diseases, including orthopedic diseases [7]. Known forms of programmed cell death include apoptosis, necrosis, pyroptosis, and ferroptosis. Among these, ferroptosis is distinct as an iron-dependent cell death mode. The molecular mechanisms regulating ferroptosis mainly involve three aspects: (1) abnormal phospholipid metabolism: phospholipids containing polyunsaturated fatty acids are more prone to peroxidation, and under the catalysis of long-chain acyl-CoA synthetase 4, they are transferred to the cell membrane phospholipid layer, accelerating peroxidation of the plasma membrane and inducing ferroptosis [8]; (2) abnormal iron metabolism: iron can catalyze lipoxygenases and other metabolic enzymes, leading to phospholipid peroxidation and reactive oxygen species generation [9-10]; moreover, phospholipid hydroperoxides, as executors of ferroptosis, react with ferrous and ferric ions to produce free radicals that propagate lipid peroxidation [11]; (3) classic glutathione peroxidase 4 (GPX4) antioxidant dysregulation: GPX4, a selenoprotein, converts glutathione to oxidized glutathione, enhancing cellular antioxidant capacity and eliminating lipid peroxides to protect cell membrane integrity [12]; it also reduces cytotoxic lipid peroxides to corresponding alcohols, decreasing lipid peroxide accumulation [13]. Conversely, when GPX4 expression is inhibited, accumulation of lipid peroxides is a key marker of ferroptosis [14].

According to current research, positive regulation of ferroptosis can ... (the text continues, but the introduction section is cut off in the provided text).