Iron is an important component of many enzymes in the body, which is involved in the transport and storage of oxygen, immune regulation, DNA metabolism, inflammatory response and other processes (10). However, when the ferrous in plasma exceeds the binding capacity of transferrin, it will lead to the accumulation of a large amount of free iron, which will cause iron overload. Iron overload is an essential condition in the process of ferroptosis. A study has shown that (14) when ferrous ions are in excess, they will interact with H₂O₂ to undergo the Fenton reaction, which gives rise to a large accumulation of ROS and peroxidation of normal cells, ultimately leading to cell death. The reasons for iron overload may be: (1) Excessive intake of exogenous iron, such as for patients with aplastic anemia, repeated long-term blood transfusion will lead to the body’s iron levels excessive. (2) Iron metabolism related gene mutation, such as hereditary hemochromatosis (HH) is an autosomal recessive hereditary disease, which is characterized by a decrease in hepcidin activity caused by HFE gene mutation, resulting in an increase in iron into the blood (15). (3) Ineffective hematopoiesis. β-thalassemia is the most common cause of ineffective hematopoiesis. Studies have pointed out that (16, 17) the cause of iron overload in β-thalassemia is mainly caused by the increase of ineffective erythropoiesis, which leads to the continuous high expression of ferroportin (FPN) on the surface of small intestinal villus cells, so the absorption of iron is increased. Furthermore, menopause, obesity and excessive ingestion of vitamin C have also been documented to augment the susceptibility to iron overload (18–20).

Lipid peroxidation is related to the process of lipid peroxidation, which is mediated by free radicals and occurs on cell membranes and organelle membranes. Lipids constitute the main components of cell membranes and play a key role in maintaining cell structure and physiological functions. The cell membrane contains a large amount of polyunsaturated fatty acids (PUFAs), which are easily oxidized due to their special structure and are the main targets of ROS attacks, especially arachidonic acid (AA) and adrenergic acid (AdA) (21). The process of lipid peroxidation includes three steps, the first free AA or AdA is activated by acyl-CoA synthetase long-chain family member 4 (ACSL4) to form AA-CoA or AdA-CoA (22). Subsequently, AA-CoA or AdA-CoA was catalyzed by lysophosphatidylcholine acyltransferase 3 (LPCAT3) to synthesize AA-PE or AdA-PE with phosphatidylethanolamine (PE) in membrane phospholipids (23). Finally, lipid peroxidation occurred in AA-PE or AdA-PE. Lipid peroxidation can be mediated via two pathways (24). One is the ROS non-enzymatic pathway. When the ferrous ion concentration in the cell is excessive, the occurrence of the Fenton reaction will lead to a significant accumulation of ROS. ROS reacts with PUFAs in the lipid membrane and induces lipid peroxidation to form lipid peroxides, such as malonaldehyde (MDA). High concentrations of lipid peroxides can cause oxidative stress in cells, which is a necessary condition for the initiation of ferroptosis (25). The other is lipoxygenases (LOXs) enzymatic pathway, LOXs are iron-containing proteins that directly oxidize PUFAs on the biofilm to participate in ferroptosis, causing rapid and severe damage to the cell membrane (26). Recent studies have shown that ACSL4 mutations are associated with the occurrence and development of many diseases, such as tumors, cardiovascular diseases, and bone diseases (27–29). ACSL4 is a key protein in the process of ferroptosis, which can induce lipid peroxidation of polyunsaturated fatty acids and promote ferroptosis. Dolma S et al. found that (30) knocking out the ACSL4 gene can effectively reduce glutathione peroxidase 4 inhibitor-induced ferroptosis, which may be a new idea to inhibit ferroptosis.

Oxidative stress is a pathological state of the imbalance between peroxidation and antioxidant system in the body. Under normal circumstances, even minor fluctuations in the redox balance within the biological system can be promptly sensed by a specialized “sensor”. After that, the downstream signal transduction cascade is activated to regulate the metabolic process. However, when the intracellular H₂O₂ exceeds a certain threshold, the integrity of the cell begins to be affected (31). JIA (32) and HE (33) et al. found that intracellular ROS production was significantly increased in a high-iron environment and increased in a dose-dependent manner with iron. When a large amount of iron is accumulated in the body, the ferrous in the cells will increase, because of the instability and high reactivity of ferrous, Fenton reaction occurs between ferrous and H₂O₂, resulting in the production and aggregation of hydroxyl (OH) (14). The imbalance in the rate of ROS production can lead to oxidative stress, which in turn produces free radicals, which can cause damage to cellular DNA, proteins, and enzyme activity, and ultimately cause cell death (34). Glutathione (GSH), which is constituted by glutamic acid, cysteine, and glycine, serves as a crucial antioxidant and free radical scavenger within cells. Glutathione peroxidase 4 (GPX4), being the fourth member of the selenium-containing GPX family, is regarded as an enzyme isomer that is closely associated with ferroptosis and functions as a core regulator of ferroptosis. The primary reason for this is that it is the sole enzyme in the cell capable of reducing lipid peroxides (35). It can convert lipid peroxides into lipid alcohols, thereby impeding the generation of toxic ROS (36). Nevertheless, when GSH is depleted, the activity of GPX4 is lost and the antioxidant capacity of cells is diminished, which will accelerate the elevation of lipid peroxidation within cells and give rise to ferroptosis (37).

As an essential trace element for the human body, iron ions are involved in a variety of physiological activities and metabolic processes in cells. Iron in food is first absorbed by epithelial cells in the small intestine and converted into ferrous, which is then transferred into the cytoplasm of intestinal epithelial cells by divalent metal ion transporter (DMTI) to release. The released ferrous enters the labile iron pool (LIP) or is stored in ferritin in a stable form of iron ions to meet the physiological metabolic function of cells. FPN, as the only membrane transporter that mediates iron ion export, can release excess iron into the blood and eventually be utilized in various tissues and organs. It is expressed on the cell membranes of liver, duodenal epithelial cells and reticuloendothelial macrophages (38). When the body accumulates a large amount of iron due to various factors, the excess ferrous ions will interact with H₂O₂ and cause Fenton reaction to cause death. And when FPN is mutated, it will also cause abnormal iron metabolism and lead to ferroptosis (39). Hepcidin is a hormone-like polypeptide synthesized and secreted by liver cells. Nemeth et al. (40) found that in the process of iron metabolism regulation, the combination of FPN and hepcidin can lead to the degradation of FPN, so that iron cannot be discharged into the blood circulation, and reducing the iron level in the blood. Nemeth et al. (40) found that the combination of FPN and hepcidin can reduce the level of iron in the blood during the regulation of iron metabolism. This is because the binding of hepcidin to FPN1 can accelerate the ubiquitination, internalization and degradation of FPN1, and reduce the serum iron concentration by reducing the absorption of iron by intestinal epithelial cells and reducing the release of iron by hepatocytes and macrophages. Therefore, regulating iron homeostasis through hepcidin may be a new target for the treatment of ferroptosis. However, when the level of hepcidin increases significantly, the concentration of iron ions in plasma decreases, resulting in iron not being fully used for the synthesis of hemoglobin, resulting in anemia (41). At the same time, in the state of chronic inflammation, the expression of hepcidin may increase, which inhibits the absorption and utilization of iron and further aggravates anemia (42). This may be a side effect of hepcidin. Therefore, it is necessary to strictly control the intake of hepcidin-like drugs to maintain normal iron homeostasis and prevent anemia caused by iron deficiency and tissue damage and organ failure caused by excessive iron.

Ferritinophagy, which is mediated by nuclear receptor coactivator 4 (NCOA4), is an important part of the ferroptosis pathway. It can specifically recognize ferritin heavy chain (FTH) and transport it to lysosomes to complete autophagy (13). Ferritinophagy is the only way for intracellular ferritin to be converted into available iron ions. In the process of ferritinophagy, the ferritin protein itself is not converted to iron ions. Rather, the protein is degraded and recycled and the iron ions that were stored are released. However, under certain pathological conditions, ferritinophagy can be over-activated and cause cell damage. Li et al. found that (54) that deferoxamine can inhibit the expression of NCOA4 in cardiomyocytes of diabetic rats, thereby inhibiting ferritinophagy. At the same time, studies have shown that (55, 56) hypoxia inducible factor-1α (HIF-1α) and EC-Exos from endothelial cells can also inhibit ferroptosis by inhibiting ferritinophagy. In addition, mitophagy can remove damaged mitochondria in cells to maintain cell homeostasis. In recent years, a study has pointed out that it can cause iron and ROS accumulation, and induce ferroptosis (57). The specific mechanism is shown in Figure 1 .

TRF, denoting transferrin, and TfR, signifying transferrin receptor, upon their combination, facilitate the translocation of iron ions present in the bloodstream into cells. The iron ions that have entered the cells are converted into ferrous ions under the catalytic action of STEAP3. DMT1, namely divalent metal transporter 1, is capable of discharging ferrous ions into the cytoplasmic compartment. The released ferrous ions then enter the labile iron pool. In the event of an excessive iron ion concentration, the ferrous ions will interact with H₂O₂, thereby triggering the Fenton reaction and culminating in ferroptosis. FPN1, which refers to Ferroportin, is responsible for releasing surplus iron into the blood. Hepcidin, on the other hand, can suppress the function of FPN and consequently reduce the iron levels in the blood. PUFAs, or polyunsaturated fatty acids, are ultimately converted into lipid peroxides under the influence of diverse enzymes, giving rise to oxidative stress and subsequent cell death. GPX4, that is glutathione peroxidase 4, in conjunction with System Xc-, undertakes an antioxidant role. When System Xc- is inhibited, the synthesis of intracellular glutathione (GSH) is diminished, leading to an augmentation in peroxides and consequent cell death. Erastin, ATF3, and P53 are capable of inhibiting System Xc- and thereby inducing ferroptosis. FSP1, or ferroptosis-suppressor-protein 1, and GCH1, which is GTP cyclohydrolase-1, possess the property of inhibiting ferroptosis.

Deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFS) are the three iron chelators currently used in clinical practice, among them, DFO is the longest and most widely used iron chelator (80). A Study has confirmed that (81) DFO can improve iron overload and restore bone-related indicators. DFO is a HIF-1α activator with dual protective effects. It not only inhibits ferroptosis in osteoblasts, but also protects osteoclasts from ferroptosis by reducing RANKL-induced ferritin autophagy. Therefore, DFO can reduce ferroptosis by reversing elevated iron levels in OP patients. There is also evidence that (82) DFO can promote the differentiation of BMSCs into osteoblasts through the Wnt/β-catenin signaling pathway. Ding et al (83) confirmed that DFO can activate the PI3K/AKT signaling pathway. The activation of the PI3K/AKT signaling pathway is also considered to directly promote the osteogenic differentiation of stem cells, so, it can be speculated that the promotion of DFO osteogenesis may be related to the activation of the PI3K/AKT signaling pathway (84). DFP is the first clinically available oral iron chelator. Link et al. found that (85) DFP can reduce oxidative stress damage caused by iron overload. Naves et al. found that (86) DFP can reduce the concentration of iron ions in osteoblasts and increase the activity of alkaline phosphatase (ALP), which is stronger than DFO. DFS is mainly used in patients over 2 years of age with chronic iron overload in children with thalassemia and iron overload caused by other transfusion-dependent diseases. A study has shown that (87) DFS can inhibit osteoclast ferroptosis by inhibiting the activity of NF-κB pathway, while DFO and DFP have no such effect. Therefore, it is of great significance to use different iron chelators for the prevention and treatment of osteoporosis.

Melatonin (MT), N-acetyl-5-methoxytryptamine, was originally considered to be a hormone that regulates biological rhythms. In recent years, a study has found that (86) MT not only has the effect of regulating sleep, but also has anti-inflammatory, anti-oxidation, anti-osteoporosis, anti-tumor and other effects. The main mechanisms of the effect of MT on bone metabolism are as follows: (1) Promote the proliferation and differentiation of osteoblasts. MT can promote the proliferation and differentiation of osteoblasts through direct or indirect ways, thereby delaying the process of OP. Maria et al (88) found that MT could increase the expression of RUNX2 and inhibit the expression of peroxisome proliferators-activated receptors (PPARγ) and RANKL by adding MT to the co-culture model of BMSCs and monocytes, which indicated that MT could promote the differentiation of BMSCs into osteoblasts. Chen et al. found that (89) MT can reduce the level of oxidative stress in BMSCs of osteoporotic rats and indirectly promote osteoblast differentiation, thereby improving OP symptoms. Guan et al. found that (90) MT can weaken the osteogenic inhibition of BMSCs referred to by lipopolysaccharide and indirectly promote osteogenic differentiation, and this effect may be achieved through the TLR4/NF-κB signaling pathway. At the same time, it has been found that (91) MT can significantly promote the expression of bone morphogenetic protein (BMP), thereby promoting the proliferation and differentiation of osteoblasts and increasing bone mass. In addition, a study has shown that (92) MT can promote bone formation by increasing the expression of osteocalcin (OCN), thereby promoting the proliferation and migration of MSCs and enhancing the proliferation and differentiation of osteoblasts, and ultimately increase bone mass.(2) Inhibit osteoclast differentiation formation. Zhou et al. (93) found that MT can reduce intracellular ROS and inhibit osteoclast formation, thereby reducing bone resorption and increasing bone mass. In addition, they also speculated that MT may inhibit osteoclast differentiation by regulating NF-κB signaling pathway. Under the condition of high glucose, the level of iron autophagy in osteoblasts increases, which promotes the occurrence of ferroptosis. One study indicates that (94) MT can inhibit ferroptosis of osteoblasts under high glucose conditions, the mechanism is not clear, which may be through up-regulating the expression of miR-550a-3p. MiR-550a-3p is correlated with changes in bone tissue morphological parameters and microstructural parameters, which may provide a reference for bone quality assessment and fracture risk prediction of OP.

Ferrostatin-1 (Fer-1) is an aromatic amine antioxidant and an effective ferroptosis inhibitor. It can specifically prevent the accumulation of ROS produced by lipid peroxidation. Wu et al (95) induced ferroptosis in mouse renal tubular epithelial cells by high glucose, and found that the content of ferrous and MDA in the kidney tissue of mice in the Fer-1 intervention group decreased, and the GSH content increased significantly. This indicates that Fer-1 can increase the concentration of GSH in diabetic kidney tissue, inhibit lipid oxidation and iron overload, thereby improving ferroptosis. In addition, they also found that the protein expression levels of GPX4 and SLC7A11 in this group of mice were up-regulated, which further indicated that Fer-1 inhibited ferroptosis by up-regulating the activity of GPX4 and SLC7A11. Jiang et al. (96) found that iron overload destroyed the redox balance of cells by establishing an iron overload mouse model, which was mainly manifested by excessive intracellular ROS, lipid peroxidation, increased MDA, and decreased superoxide dismutase (SOD) and GSH. In addition, they also found that the levels of OCN, OPN and P1NP in this group of mice serum were decreased, while the use of Fer-1 could improve the above-mentioned peroxidation state and significantly increase the level of OPN. Zhang et al. discovered that (64) high glucose suppresses the osteogenic differentiation and cell proliferation activity of BMSCs, leading to the accumulation of ROS and lipid peroxides within cells. However, following the addition of Fer-1, the levels of ROS and lipid peroxides declined, implying that the inhibitory effect of high glucose on the osteogenic differentiation of BMSCs might be induced by ferroptosis. So, Fer-1 may provide new ideas for the prevention and treatment of osteoporosis in the future.

Vitamin D is essential for bone mineralization and bone quality maintenance. Among them, 1,25 (OH) D is the most active metabolite of vitamin D, which plays an anti-osteoporosis role by binding to vitamin D receptor (VDR) (97). Xu et al. (98) found that VDR activation can decrease osteoblast ferroptosis by stimulating Nrf2/GPX4 signaling pathway. Zileuton is a N-acetyl-5-methoxytryptamine that inhibits the production of ROS in the cytoplasm and has a significant protective effect on erastin-induced ferroptosis (99). In addition, Maresin 1 is a polyunsaturated fatty acid necessary for human body. Zhang et al. found that (100) Maresin 1 can protect osteoblasts from ferroptosis in high glucose environment by affecting Nrf2 signaling pathway, thereby improving osteogenic ability. A summary of the various Western medicines is found in Table 1 .

Icariin is a flavonoid compound in epimedium, which is widely used in bone metabolic diseases and has pharmacological effects such as anti-osteoporosis and anti-tumor (101). Li found that (102) the level of MDA in BMSCs added with icariin decreased and the level of SOD increased, which indicated that icariin can inhibit the accumulation of ROS in BMSCs caused by Erastin to reduce apoptosis. Fu et al. (103) found that icariin can delay the inhibition of cystine metabolism by down-regulating FPN1 and up-regulating GPX4, inhibit lipid peroxidation and iron metabolism, and ultimately reduce ROS to inhibit osteoblast death. In addition, they also observed that icariin can regulate osteoblast proliferation and differentiation by increasing osteoblast Runx-2 and ALP protein expression. In addition, a study has shown that (104) icariin can inhibit mitochondrial oxidative stress and ferroptosis by targeting Nrf2. Therefore, icariin can prevent bone loss caused by iron overload and thus play a role in the prevention and treatment of osteoporosis.

Baicalein is a monomeric compound mainly derived from the root of Scutellaria baicalensis Georgi. It has antioxidant, anti-inflammatory, anti-tumor and anti-allergic properties (105). Xie et al. found that (106) baicalein is a natural ferroptosis inhibitor, which can inhibit erastin-induced GPX4 degradation, thereby protecting cells from membrane lipid peroxidation. One study indicates that (107) the mechanism of baicalein inhibiting ferroptosis and reducing bone damage may be related to the up-regulation of SLC7A11/GPX4 pathway and the promotion of BMSCs proliferation and osteogenic differentiation. Guo found that (108) baicalein at an appropriate concentration can increase the expression of GPX4 and β-catenin protein in ferroptosis model cells, increase the activity of cell proliferation, and then inhibit ferroptosis. This reveals that baicalein may up-regulate GPX4 through the Wnt/β-catenin signaling pathway to inhibit ferroptosis.

Quercetin is a natural flavonoid compound that is widely found in many Chinese herbal medicines. Quercetin and its derivatives have anti-inflammatory, antioxidant, antibacterial, and anti-tumor effects (109), among them, quercetin has obvious advantages in anti-oxidation and anti-inflammatory. A Study has pointed out that (110), quercetin mainly enhances its antioxidant properties by regulating GSH levels, regulating enzymes or antioxidants. Yin et al.found that (111) quercetin can reduce the expression of ATF3, restore the activity of GPX4, and reduce ROS, thereby reducing the inflammatory response. At the same time, recent research indicates that (112) quercetin can improve lipopolysaccharide-induced osteoblast apoptosis, which may be achieved by regulating MAPK and Wnt/β-catenin pathways, thereby promoting osteoblast proliferation, differentiation and mineralization.

Myricitrin is a potent antioxidant isolated from plants, which has analgesic, anti-inflammatory, neuroprotective and antioxidant effects (113). A study has found that (114), myricitrin can reduce ROS production, aldehyde levels and increase GSH activity, thereby reducing the inflammatory response, and it can improve the microstructure of bone. Obviously, the therapeutic effect of myricetin on osteoporosis is related to the regulation of oxidative stress-mediated ferroptosis. Wang found (115) that myricitrin can inhibit RANKL-induced osteoclast precursor cells to osteoclast differentiation and maturation, and the degree of inhibition is proportional to the concentration of myricitrin. Therefore, inhibiting the formation and activity of osteoclasts is of great significance for the development of new drugs for the treatment of OP.

A study have shown that (116) low concentration of benzoylaconitine can increase the expression of GPX4 and β-catenin protein in osteoblasts induced by Erastin, and effectively inhibit the occurrence of ferroptosis. Duzhong-duanduan, luteolin and echinacoside can significantly inhibit the expression of p53 protein, reduce osteoblast apoptosis, promote osteogenic differentiation, thereby alleviating osteoporosis (117–119). Phytol can prevent the accumulation of ROS by regulating the Nrf2/HO-1 pathway and restoring antioxidant enzymes, thereby improving osteoporosis (114).In addition, some TCMs, such as Qing’e pill, Bugu Shengsui Decoction, Zuogui Pills, etc., can prevent ferroptosis by regulating iron overload and lipid LOXs roxidation, thereby playing a role in preventing and treating osteoporosis (120–122). A summary of the various TCMs is found in Table 2 .