SystemXc-is a transporter that is located on the cell membrane. The transportation and exchange of cystine can be facilitated by System Xc-, which also allows for the transport of glutamate (Fantone et al., 2024). Cystine enters cells and is reduced to cysteine, which combines with glutamate and glycine to form GSH. System Xc-controls GSH production through disulfide bonds between solute carrier family 7 member 11 (SLC7A11) and solute carrier family 3 member 2 (SLC3A2) (Liu et al., 2020a; Jiang and Sun, 2024). SLC7A11 facilitates cystine to glutamate transfer in a 1:1 ratio (Fantone et al., 2024). Cysteine is subsequently reduced to cysteine by thioredoxin reductase 1 (TrxR1) (Conrad and Sato, 2012; Mandal et al., 2010). SLC3A2 plays a crucial role in regulating the transport function of SLC7A11 and ensuring its stability (Nakamura et al., 1999).

Glutamate, cysteine, and glycine form GSH, with glutamate-cysteine synthase and glutathione synthase as catalysts for its production (Bansal and Simon, 2018; Forman et al., 2009). Within the cell, most of the space is occupied by reduced glutathione (Diaz-Vivancos et al., 2015). Glutathione disulfide (GSSG) is the most common oxidized form of glutathione. Both reduced and oxidized forms of glutathione are capable of undergoing interconversion (Niu et al., 2021). The progression of ferroptosis is contingent upon the levels of GSH((Guo et al., 2021)). GSH is an antioxidant that neutralizes ROS, inhibits lipid peroxides, and maintains cellular redox equilibrium by adjusting NADP/NADPH and GSH/GSSG ratios (Diaz-Vivancos et al., 2015; Sahoo et al., 2022; Zhong et al., 2022). GSH acts as a cofactor for GPX4, preventing lipid peroxidation and ferroptosis by converting LOOH into LOH (Jia et al., 2020).

Cysteine in GPX’s protein superfamily redox residues catalyzes redox processes (Flohé et al., 2022; Xie et al., 2023). GPX4 can prevent lipid oxidation and biofilm destruction by using GSH’s reducing equivalent (Ursini et al., 1982; Nishida et al., 2022). GPX4 reduces intracellular peroxides, especially phospholipid hydroperoxides (Ursini et al., 1982; Thomas et al., 1990). GPX4 is most typically expressed in the cytosol, followed by mitochondrial and nuclear classes. Apoptosis resistance is mostly due to mitochondrial GPX4 (Liang et al., 2009). GPX4 is one of the main regulators performing ferroptosis. Gpx4 safeguards mitochondria from peroxide damage (Liu et al., 2024). GPX4 loss or malfunction causes intracellular peroxide buildup and ferroptosis (Xie et al., 2023). GSH functions as a crucial cofactor for GPX4, inhibiting lipid peroxidation and ferroptosis through the reduction of LOOH to LOH (Li FJ. et al., 2022).

Glucose serves as a primary energy source, transformed into pyruvate through glycolysis, then entering the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) (Liu J. et al., 2021; Nie et al., 2020). During anoxia, the enzyme lactate dehydrogenase catalyzes the conversion of pyruvate into lactate (Sonveaux et al., 2008). Glucose 6-phosphate can also produce NADPH and biosynthetic precursors through the pentose phosphate pathway (PPP) (Lee et al., 2017; Martinez-Outschoorn et al., 2017). NADPH plays a crucial role in the transformation of oxidized glutathione into reduced glutathione (Dong et al., 2015; Liu et al., 2019). Mitochondria play a crucial role in energy metabolism and are responsible for generating ROS (Ashton et al., 2018; Zong et al., 2016). The occurrence of ferroptosis is closely linked to energy metabolism.

Iron deficiency is linked to inflammation, triggering production of inflammatory molecules that stimulate lipid peroxidation (Chen X. et al., 2021; Chen Y. et al., 2022; Sun et al., 2020). Ferroptosis is linked to inflammatory signaling pathways. Triggering ferroptosis with erastin or RSL3 activates the JAK-STAT pathway through IFN-γ in tumor cells (Barrat et al., 2019; Kong et al., 2021). The JAK2-STAT3 signaling pathway positively correlates with hepcidin expression, influencing systemic iron metabolism through regulation (Yang L. et al., 2020; Ren et al., 2021; Kowdley et al., 2021).

The NF-κB pathway is associated with the activation of inflammation and the innate immune response (Hoesel and Schmid, 2013). Ferroptosis is mediated by the NF-κB signaling pathway, which is activated by ferroptosis inducer RSL3, regulating System X_c ⁻ transmission and interacting with heme oxygenase 1 to metabolize heme and ferrous iron (Pulkkinen et al., 2011; Ryter, 2021). NF-κB signaling promotes ferritin heavy chain 1(FTH1) expression in response to TNF-α (Kou et al., 2013). Ferritin light chain expression (FTL) increases in lipopolysaccharide (LPS)-stimulated macrophages, limiting NF-κB signaling and reducing TNF-α, IL-1β, and inflammation (Zarjou et al., 2019).

Inflammasomes have a strong correlation with lipid peroxidation. NLRP3 inflammasomes upregulated in response to GPX4 inhibition, linked to lipid peroxidation (Xie et al., 2022). Inhibition of NLRP3 reverses oxidative stress in a lipid peroxidation model (Orecchioni et al., 2022). Suppressing NLRP3 led to increased GPX4, elevated GSH levels, and reduced phospholipid peroxides (Meihe et al., 2021). The cGAS-STING pathway interacts with ferroptosis, inducing oxidative stress and STING translocation. STING inhibition decreases ferroptosis sensitivity (Li C. et al., 2021). Ferroptosis from high iron diet and GPX4 deficiency can cause pancreatic cancer in mouse models, affecting cGAS-STING signaling (Dai et al., 2020).

The MAPK pathway triggers ferroptosis through inflammatory activation, inducing pro-inflammatory cytokines, suppressing GPX4 and System X_c ⁻, and leading to neuroinflammation and cell death (Zhu et al., 2021). Excessive iron activates ERK1/2 and p38, causing oxidative stress and peroxide formation through the MAPK pathway (Salama and Kabel, 2020; Ikeda et al., 2019). Application of antioxidants resulted in the inhibition of the MAPK pathway and a reduction in peroxide concentration (Fu et al., 2018; Cavdar et al., 2020).

Hypoxia is a physiological reaction that occurs due to various internal or external conditions (Tano and Gollasch, 2014; Chen G. et al., 2022; McClelland and Scott, 2019). Within the hypoxic environment, some distinct signaling pathways are triggered, mostly through the mediation of hypoxia-inducible factor (HIF) (Schito and Semenza, 2016; Kaelin and Ratcliffe, 2008). Oxidative stress increases under hypoxia and ROS accumulation is the main cause of ferroptosis (Honda et al., 2019). The HIFs family has three isoforms: HIF-1, HIF-2, and HIF-3. HIF-1 forms in extreme oxygen deprivation, while HIF-2 forms in moderate oxygen deprivation (Koh and Powis, 2012; Cowman and Koh, 2022).

The HIFs family has three isoforms: HIF-1, HIF-2, and HIF-3. HIF-1 forms in extreme oxygen deprivation, while HIF-2 forms in moderate oxygen deprivation (Zheng X. et al., 2023). The inhibiting impact of this substance affects both normal cells and malignant cells (Kumar and Choi, 2015; Pan et al., 2021). HIF-1α prevents ferroptosis by stabilizing SLC7A11 and activating hypoxia response elements that control glutathione metabolism (Hu et al., 2022; Lin Z. et al., 2022). HIF-2α acts as a positive regulator of ferroptosis (Johansson et al., 2017; Singhal et al., 2021). HIF-2α triggers ferroptosis by activating genes like ACSL4 Cigarette smoke exposure boosts HIF-2α, leading to myotube apoptosis (Zhang L. et al., 2022). Further investigation is needed to investigate the diametrically opposite effects of HIF-1α and HIF-2α.

Epigenetics is a dynamic process that includes DNA methylation, histone modification, and non-coding RNA (ncRNA) regulation, which allows gene expression to change without changing the DNA sequence (Wang N. et al., 2023; Cavalli and Heard, 2019). In addition to being impacted by traditional signaling pathways, ferroptosis-related genes are also controlled by epigenetic processes.

Lysosomes are attached to autolysosomes during autophagy in order to facilitate cellular turnover and metabolism. The breakdown of internal metabolic activities during autophagy results in the creation of autophagosomes (Luo and Tao, 2020; Zhou et al., 2020). There is growing evidence that ferroptosis requires autophagy’s involvement (Mizushima and Levine, 2020). T Ferroptosis-inducing medications can cause GPX4 degradation by autophagy, which is subsequently mediated by the enzyme acid sphingomyelinase, which is essential for the metabolism of sphingolipids (Thayyullathil et al., 2021). Autophagy causes the amount of free iron in the bodies of mice with subarachnoid hemorrhage to increase, which leads to ferroptosis of free iron in their bodies grow, which ultimately results in ferroptosis (Patil et al., 2021). A few results that are comparable to one another demonstrate that autophagy increases ferritin degradation (Hou et al., 2016; Liu et al., 2020b; Tian et al., 2020; Ma et al., 2017).

Pyroptosis is an inflammatory form of cell death that relies on the involvement of caspases (Chen et al., 2019). It is characterized by a similar pattern to ferroptosis, involving membrane damage, accompanied by ROS accumulation and iron dependence (Xu R. et al., 2021). ROS, via iron-dependent activation, facilitate caspase-related pathways, leading to the degradation of ferritin and the initiation of pyroptosis (Zhou et al., 2018).

Cuproptosis is characterized by an aberrant metabolism of copper ions. High levels of copper ions can lead to protein toxicity, which can ultimately result in the death of cells (Tsvetkov et al., 2022). Mitochondria link ferroptosis with cuproptosis. Mitochondria play a significant role in the production of ROS and directly contribute to cell death caused by iron. Additionally, in the mitochondrial TCA cycle, the process of glutaminolysis, which leads to a shortage of cysteine, is also responsible for cell death caused by iron (Gao et al., 2019b). Observations revealed morphological alterations in mitochondria affected by cuproptosis, with mitochondrial respiration and acting a significant part in this process (Tang et al., 2022). Furthermore, GSH serves as a central point linking iron toxicity with copper toxicity. A study has proven that the drugs sorafenib and erastin, which are ferroptosis inducers, increase cell death in primary hepatocellular carcinoma cells when combined with a copper ionophore (Wang W. et al., 2023). This effect is achieved by decreasing the synthesis of GSH. GSH also forms a complex with copper to decrease the buildup of copper within cells (Liu and Chen, 2024).

Apoptosis in programmed cell death is one of the most intensively studied. Initiation of apoptosis activates caspase (Yuan and Ofengeim, 2024). Caspases can cause cells to form apoptotic typical morphology, such as nuclear lysis and rounding of the cell shape (Rajagopalan et al., 2024). Ferroptosis was discovered as a novel programmed cell death independent of apoptosis because it caused cell death without caspase activation and could not be reversed by caspase inhibitors (Wu P. et al., 2023). But recent studies have found an inextricable link between iron death and apoptosis. For example, p53 apoptosis stimulating protein inhibitor (iASPP) inhibits p53-induced apoptosis, while iASPP also plays an anti-ROS role, thereby promoting Nrf2 accumulation and nuclear metastasis (Li et al., 2020). And Nrf2 is a protective mechanism against iron death. Perez et al. found that iron death is mutually exclusive with apoptosis (Perez et al., 2020). In addition, erastin induced p53 to promote apoptosis in A549 lung cancer cells (Huang et al., 2018). Erastin can also induce oxidative stress and cause caspase-9-dependent cell death (Huo et al., 2016).

Chondrocytes are the only cells that constitute articular cartilage and act to be responsible for the metabolism of the extracellular matrix (ECM) (Pettenuzzo et al., 2023). Studies have demonstrated that chondrocytes, which are affected by inflammation, tend to accumulate ROS and have modified expression of ferroptosis-related proteins in models of OA. More precisely, the expression of GPX4 and SLC7A11 in chondrocytes was reduced when inflammation was triggered by IL-1β and by creating a simulated iron overload environment. Utilizing ferroptosis inhibitors resulted in a decrease in ROS levels and a reduction in cytotoxicity (Yao et al., 2021). Another study revealed that inflammatory stimuli can disturb the iron equilibrium in chondrocytes. The expression of TfR1 was upregulated while the expression of FPN was downregulated in chondrocytes after treatment with IL-1β and TNF-α. An excess amount of iron in cartilage leads to the destruction of cartilage, resulting in oxidative stress and damage to the mitochondria (Jing et al., 2021).

From the aforementioned investigations, it is evident that there is a strong correlation between the occurrence of OA, characterized mostly by cartilage destruction, and iron depletion. Oa is a closely related disease to age and a disease that is easily disabling in chronic diseases. Inflammation, cartilage degeneration, and synovial hyperplasia can be seen in OA. Abnormal iron metabolism can directly contribute to OA by causing inflammation, in addition to the indirect damage to cartilage that is commonly associated with the condition (Burton et al., 2020). Elevated ferritin levels are one of the risk factors for OA. Imaging analysis showed a positive correlation between ferritin levels and the severity of arthritis (Cai et al., 2021; Kennish et al., 2014). One element affecting older patients’ morbidity is gender. Research has shown that OA affects older women on more occasions than older males, and that this difference is related to postmenopausal estrogen levels (Ko and Kim, 2020). Nonetheless, ferritin levels are negatively connected with estrogen levels, and iron levels in the serum of postmenopausal women are 200%–300% higher than those of non-menopausal women, according to current research. Because of this distinction, postmenopausal women experience a much higher prevalence than do men (Park et al., 2012; Zhang et al., 2001; Ke et al., 2021). There is a substantial correlation between blood problems and OA, according to a Mendelian randomization study (Xu J. et al., 2022). Hemophiliac individuals have an increase in red blood cells in the joint space because of continuous methemoglobin release and prolonged bleeding, which causes iron accumulation and ferroptosis (van Vulpen et al., 2018; Bhat et al., 2015). Patients with hemochromatosis who have OA have also been observed to accumulate iron in the joint space; dysmorphic cartilage has been restored after excess iron has been removed (Richette et al., 2010; Heiland et al., 2010).

The mechanism of OA resulting from ferroptosis involves inhibition of antioxidant pathways. In OA, inhibition of GPX4 and SLC3A2 expression has been shown (Liu H. et al., 2022; Miao et al., 2022). ECM degrades when GPX4 expression is suppressed (Miao et al., 2022). Type II collagen (collagen II) was also expressed in ECM by ferroptosis inhibitors, and this process was reversed after ferroptosis inhibitor treatment (Yao et al., 2021). Activation of Nrf2 can also prevent ferroptosis (Xu C. et al., 2022). In addition, HIF-2α stimulates lipid peroxidation and suppresses GPX4 and SLC7A11 to facilitate chondrocyte ferroptosis (Zhou et al., 2021). Piezo1, a mechanosensitive ion channel, is also involved in iron metabolism in OA by inhibiting the GSH-GPX4 axis (Wang S. et al., 2022; Ma et al., 2021). Overall, ferroptosis in OA involves multiple aspects. Among them, inflammation and antioxidant inhibition are the main causes of OA.

AS is a rheumatic bone disease caused by inflammation. The location of AS is centered on the sacroiliac joint and affects the surrounding joints (Thomas and Brown, 2010; Rostom et al., 2010). The main symptom of AS is inflammatory spinal pain, accompanied by bone erosion and ligamentous osteophytes (Tam et al., 2010). Although ferroptosis caused by lipid peroxidation is rarely reported in AS, it is not difficult to find from the study of specific serum proteomics and metabolome student markers in AS patients that the main reasons affecting ferroptosis in AS are iron levels and oxidative stress response. Studies have reported that serum TfR1 levels are low in AS patients, while platelet iron content remains high (Fischer et al., 2012; Feltelius et al., 1986). Decreased antioxidant capacity is one of the characteristics of AS. A study on serum oxidation and antioxidation in AS patients highlighted decreased antioxidant capacity and increased oxidative stress index in AS patients (Karakoc et al., 2007). AS patients with metabolic syndrome are more susceptible to oxidative stress (Pishgahi et al., 2020). GPX, which is closely associated with ferroptosis, was found to have decreased expression in mouse models of AS (Feng et al., 2020; Dong, 2018).

GA is characterized by hyperuricemia and urate deposition (Zhang Y. et al., 2022). Abnormal iron metabolism and antioxidant imbalance are one of the pathogeneses of GA. A Mendelian randomization study revealed a relationship between ferritin and risk of gout. This study is the first to demonstrate a positive association between serum ferritin and the risk and frequency of gout (Fatima et al., 2018). In a study on the association between markers of iron status and the risk of hyperuricemia in Chinese adults, the researchers found a positive correlation between serum ferritin, transferrin and hyperuricemia (Li et al., 2018). The same results were found in another US National Health and Nutrition Examination Survey (Ghio et al., 2005). Maintaining close to iron deficiency levels has also been demonstrated as a protective factor in GA (Facchini, 2003). Xanthine oxidase (XO) is the only source of urate. XO enhances its activity when combined with iron (Jomova et al., 2024; Maiti et al., 2022). A direct relationship between iron and uric acid is therefore concluded.

The autoimmune illness RA is typified by progressive bone damage and synovial hyperplasia. Teratogenicity in RA is caused by pannus development, chronic inflammation, and bone loss. Recent research has demonstrated that characteristics unique to ferroptosis can also be seen in RA, and these discoveries have established a connection between RA and ferroptosis. Treatment for RA may be improved by having a better understanding of the general process of ferroptosis in RA.

Abnormal iron metabolism is the first element leading to ferroptosis in RA. A Mendelian randomization study of genetic data from a large genome-wide association study of 257,953 individuals suggests that individuals with genes associated with higher iron levels may have a lower risk of RA (Wu, 2024). Another Mendelian randomization trial yielded similar results, showing a negative correlation between iron intake and RA (Wang et al., 2024a). According to a clinical investigation, RA patients had considerably lower serum iron levels and higher serum TFR values (Stefanova et al., 2018). Peripheral blood iron levels are lower in patients with severe RA (Wu et al., 2022).

Another important factor in the progression of RA is ROS, which has been shown to rise approximately fivefold in the mitochondria from whole blood and monocytes of RA patients. The main manifestations of ROS include increased oxidative stress and decreased antioxidant levels (Ferreira et al., 2021). Oxidative stress occurs when there is an imbalance between ROS production and the body‘s antioxidant defenses. In RA, elevated ROS levels were observed in synovial fluid, blood, and affected joint tissues. These ROS contribute to joint inflammation and injury by promoting activation of pro-inflammatory signaling pathways, inducing cytokine production, and enhancing proliferation of fibroblast-like synoviocytes (FLS). The resulting inflammatory and oxidative damage leads to degeneration of cartilage and bone, which are hallmark features of RA (Mueller et al., 2021). The immune system plays a crucial role in RA, where T cells, B cells, and macrophages contribute to a chronic inflammatory state. Oxidative stress can affect the function and survival of these immune cells. For example, ROS can modulate T cell activation and differentiation, skewing immune responses toward more inflammatory features (Hassan et al., 2011). High levels of inflammation trigger lipid peroxidation, and excess ROS also generate pannus at home, and such circulatory effects accelerate the progression of RA (Phull et al., 2018; Zhou et al., 2012). During RA, macrophages release a significant number of inflammatory factors. TNF-α has the most intricate role among them all. One the one hand, as previously mentioned, TNF-α can increase inflammation by inducing ROS generation through NADPH oxidase (Latchoumycandane et al., 2012). TNF-α has been observed to stimulate GSH production and cystine absorption, however. Long-term TNF exposure can prevent NADPH Oxidase (NOX) from producing ROS, shielding FLS from ferroptosis (Wu et al., 2022).

The endoplasmic reticulum (ER) is the major organelle responsible for protein synthesis and lipid metabolism in eukaryotic cells. ER stress (ERS) refers to a series of pathological conditions such as overload of folding mechanisms and disruption of redox balance that occur during protein synthesis in the ER (Tabas and Ron, 2011). The unfolded protein response (UPR) is a compensatory response initiated in the ERS state (Walter and Ron, 2011). Evidence suggests that in the setting of RA, inflammation provokes ERS and proteins are synthesized via UPR (Park et al., 2014). ERS shares signaling pathways with ferroptosis, which makes the role of ERS have to be considered when studying ferroptosis in RA (Li C. et al., 2023). Glucose-regulated protein 78 (GRP78) promotes aberrant protein breakdown under UPR in the ERS state (Grootjans et al., 2016). GRP78-specific antibodies were identified in 63% of RA patients (Bläss et al., 2001). ERS and increased GRP78 expression can be brought on by ferroptosis inducers. P53 functions as a tumor suppressor gene in ferroptosis and ERS. It has been discovered that p53, which induces cell cycle arrest to promote chondrocyte death, is substantially expressed in RA patients (Ghosh et al., 2012; Takatori et al., 2014; Hong et al., 2017).

The skeleton of the human body is always in a state of dynamic balance. Osteoblasts (OBs) and osteoclasts (OCs) are key players in this balance and occupy approximately 90% of the skeletal composition (Cui et al., 2022). Different cells are used to differentiate OBs from OCs. Bone marrow-derived mesenchymal stem cells (BMSCs) are the source of OBs, which is a component of bone production. Originating from the monocyte/macrophage lineage of hematopoietic cells, OCs is the main factor for bone resorption and is abundant in mitochondria and lysosomes (Boyce, 2013; Kim JM. et al., 2020; Sommerfeldt and Rubin, 2001). An imbalance between the production and resorption of bone results in OP, a metabolic bone disease that increases the risk of fractures. Ferroptosis is implicated in the pathophysiology of OP, according to numerous studies (Yang et al., 2022).

BMSCs serve as precursors for the generation of OBs (Lin et al., 2019). Runt-related transcription factor 2 (Runx2) regulates BMSCs to promote differentiation into OBs under normal physiological conditions. Other transcription factors that regulate differentiation into OBs include alkaline phosphatase (ALP) and osteocalcin (OCN) (Komori, 2022). The accumulation of body iron leads to an increase in ferritin expression in BMSCs, which inhibits transcription factors crucial for osteoblast development (Balogh et al., 2016). Similar ones have now been observed in a series of experiments: ferroptosis downregulates the OBs phenotype and promotes OBs death (Xu P. et al., 2022; Ma et al., 2020); inhibition of PI3K-Akt-mTOR prevented ferroptosis in BMSCs and upregulated Runx2 and ALP expression (Lan et al., 2022a); and several closely related pathways, including GPX4 and Nrf2, can regulate ferroptosis in OBs (Messer et al., 2009). The OBs ferroptosis process is also influenced by other gene expressions. In an in vitro investigation, iron mortality was noted in OBs treated with ferric ammonium citrate, and the genes TfR1 and DMT1, which are in charge of cellular iron uptake, were discovered to be overexpressed (Luo et al., 2022). In MC3T3-E1 cells, excess iron ions also increased the expression of the apoptosis gene and NOX4 (Tian et al., 2016).

OCs differentiate under the influence of activating the receptor activator of the nuclear factor-κB (RANK)-RANK ligand (RANKL) pathway. RANK-RANKL is a specific representation of OCs and reflects OCs number and activity. Research indicates that increased RANKL expression during iron overload conditions stimulates the development of OCs and ultimately results in OP (Yang J. et al., 2020; Ma J. et al., 2022). RANKL-induced differentiation of OCs involves ferroptosis, and the mechanism by which RANKL-induced ferroptosis in OCs is mediated is ferritin autophagy. For OCs to survive, intracellular iron levels are consequently essential. In addition, this study discovered that HIF-1α can effectively prevent osteopenia-related osteopenia by blocking ferritin autophagy (Ni et al., 2021).

Hematological diseases are also one of the causes of OP involved in ferroptosis. For example, people with hemochromatosis are more likely to have osteopenia, and some of them even develop OP, which is closely related to iron accumulation (Baschant et al., 2022). Osteoporotic fractures are more common in thalassemia patients when their bodies’ ability to excrete iron is compromised by prolonged, frequent blood transfusions and iron buildup. Studies of a similar nature have verified a positive correlation between the frequency of blood transfusions and the risk of fracture (Ekbote et al., 2021; Dede et al., 2016).

There are two types of OPs: primary and secondary. Primary OP mostly refers to senile OP and postmenopausal osteoporosis (PMOP), while secondary OP is primarily Diabetic osteoporosis (DOP) and glucocorticoid osteoporosis (GIOP). Abnormal glucose and lipid metabolism may be the pathogenesis of ferroptosis in OBs in DOP (Chen et al., 2023). The researchers discovered that reduced GPX4 expression in DOP bone tissue in mice led to cellular ferroptosis. It was also verified that turning on the Nrf2/Heme Oxygenase-1 (HO-1) pathway may undo this outcome (Ma et al., 2020). Osteocyte mortality in DOP was successfully prevented by focusing on ferroptosis or HO-1, which broke the vicious cycle between HO-1 activation and lipid peroxidation (Yang et al., 2022). Mitochondrial ferritin (FtMt) is generally considered a tool for mitochondria to regulate free iron content. In the DOP model, high expression of FtMt reduced iron-induced lipid peroxidation, whereas its expression is known to instead cause mitophagy in OBs (Wang et al., 2022b). Increased serum ferritin and decreased GPX4 expression were also observed in the mouse DOP model. Therefore, high glucose environment not only inhibits osteoblast expression, exacerbates trabecular degeneration, osteopenia, but also activates ferroptosis-related gene expression and inhibits the antioxidant system (Lin Y. et al., 2022).

The pathogenesis of PMOP is closely related to estrogen. Iron plays an important role in PMOP. In a study of 728 postmenopausal women, iron was found to be an important risk factor for the onset of PMOP (Okyay et al., 2013). Postmenopausal bone loss might be addressed by taking dietary iron supplements within reasonable bounds (Wylenzek et al., 2024). HIF-1α specific inhibitors have also been found to prevent bone loss in ovariectomy (OVX). Continuous steroid hormone administration impairs osteoblast differentiation activity and lowers antioxidant system capacity, which results in GIOP (Yang et al., 2021a). Patients receiving long-term steroid therapy are more likely to have trabecular bone destruction and osteoporotic fractures. Decreased expression activity of GPX4 and the System X_c ⁻ was found in the high-dose dexamethasone-induced GIOP model (Lu et al., 2019).

Based on these findings, we conclude that there is a close relationship between OP pathogenesis and iron metabolism, and the mechanism also involves lipid peroxidation and oxidative stress. Modulation of osteoblast and osteoclast ferroptosis is a potential treatment option for OP.

Osteosarcoma (OS) is a malignant bone tumor arising from mesenchymal cells and is mostly primary (Yu and Yao, 2024). OS can lead to persistent joint pain, limited mobility, and even susceptibility to lung metastases (Zhang et al., 2018). Epidemiological adjustment reveals that the incidence of OS is closely related to age and ethnicity. Primary OS is more common in men and occurs in the long bones of the lower extremities, with large variations in incidence across ethnic groups (Mirabello et al., 2009). In addition, the age of onset tends to be more in adolescents, which may be the result of rapid skeletal growth during adolescence, and OS is therefore more likely to occur at the ends of long bones in adolescents (Mirabello et al., 2011).

Studies have shown that ferroptosis can inhibit OS progression and reduce OS chemoresistance. The status of the System X_c ⁻-GSH-GPX4 axis is critical in OS progression. By inhibiting the demethylation of H3K9me3 at the SLC7A11 promoter region in the System X_c ⁻, the ability of the System X_c ⁻ to prevent ferroptosis can be reduced (Chen M. et al., 2021). Osteosarcoma cells are resistant to ferroptosis because of a decrease in P53, one of the tumor suppressor genes. P53 binding to SLC7A11 is inhibited and is the main cause (Wang and Pan, 2023). Zinc finger structure E-box-binding homeobox 1 (ZEB1) is involved in lipid metabolism in vivo. Overexpressed ZEB1 leads to ROS accumulation (Liu et al., 2023). In transcriptomic experiments, mitochondria from the knockdown ZEB1 group showed ferroptosis-like changes and were involved in the ferroptosis process in OS (Jiacong et al., 2023).

NcRNAs are also involved in the process of ferroptosis. It was shown that genes inhibiting ferroptosis were repressed following miR-206 overexpression in OS cell lines, whereas genes promoting ferroptosis were increased than expression (Li L. et al., 2023). MiR-188-3p targets GPX4 and its expression is reduced in OS tissues, which contributes directly to ferroptosis in OS (Li Z. et al., 2023). LncRNAs can modulate OS resistance and resist OS metastasis (Argenziano et al., 2021). Despite the fact that circRNAs development and cognition are still in their infancy, there is evidence linking circRNAs to tumor metastasis and progression (Zhang et al., 2019). It has been shown that circBLNK and GPX4 are significantly upregulated in OS tissues, promote OS progression, and avoid OS cell ferroptosis (Li Z. et al., 2023).

As a degenerative disease, IVDD is the main cause of cervical and low back pain, and about 80% of low back pain is related to IVDD (Li et al., 2024b). Nucleus pulposus (NP) and annulus fibrosus (AF) are the main components of the intervertebral disc and are the main responsible for intervertebral disc function (Le Maitre et al., 2015). Although IVDD is an age-related degenerative disease, current studies suggest that ferroptosis plays an important role in it.

Ferroptosis is involved in IVDD through multiple pathways. The first is to affect normal physiological function by interfering with iron metabolism. Patients’ disc tissue showed reduced expression of FTH (Yang et al., 2021b). Additionally, there was an iron-dose dependent degeneration of cartilage endplates (Wang W. et al., 2022). When FPN is dysfunctional in IVDD, intracellular iron is excessive, which aggravates ferroptosis-induced IVDD (Lu et al., 2021). Some small molecule compounds, such as amino acids, enzymes, and transcription factors, which target the regulation of lipid metabolism and anti-oxidation are also involved in the process of ferroptosis in IVDD. Homocysteine (Hcy), derived from methionine and cysteine, is an important substance in cellular physiology (Mudd et al., 1985). Hcy can cause many musculoskeletal diseases through cellular ferroptosis (Koh et al., 2006; Fayfman et al., 2009). Epidemiological investigation, hyperhomocysteinemia is an important risk factor for IVDD. Inhibition of GPX4 methylation prevented Hcy-guided oxidative stress and ferroptosis (Fan et al., 2023). Activating transcription factor 3 (ATF3) is a member of the ATF/CREB family of transcription factors responsible for regulating signaling pathways and cellular metabolism (Rohini et al., 2018). It has now been demonstrated that ATF3 is a positive regulator of ferroptosis (Wang et al., 2020). In tumor cells, ATF3 can inhibit System X_c ⁻ expression, and inhibit GPX4 and induce ferroptosis (Wang Y. et al., 2021). Results of a bioinformatics experiment revealed that ATF3 gene differences were located in the fourth place in the hub ferroptosis gene ranking in the spinal cord injury model (Gupta et al., 2023). And clinical observations have also found that ATF3 is highly expressed in IVDD, and the mechanism is through the inhibition of SLC7A11 and SOD2 (Li Y. et al., 2022).

Angiogenesis of vascularized granulation tissue is a major feature of IVDD, and much neovascularization is also responsible for keyboard tissue degeneration. Angiogenic vascularized granulation tissue is a major feature of IVDD, and many new vessels are found in NP and are also responsible for disc tissue degeneration (Xiao et al., 2020). As such, hemoglobin numbers were significantly higher in NP than in other surrounding tissues. When IVDD occurs, the iron content in NP is too high, which is the main cause of aggravated ferroptosis (Shan et al., 2021). Notably, HO-1 has a dual regulatory role in ferroptosis. As an antioxidant, it can inhibit ferroptosis, but at the same time, it is characterized by iron concentration dependence, which activates ferroptosis at high iron content (Fang et al., 2019; Adedoyin et al., 2018). A simultaneous increase in HO-1 and iron accumulation was found in the rat IVDD model (Zhang et al., 2021), and clinical studies have also confirmed increased HO-1 expression in NP(358). Such results are strongly associated with neovascularization. As one of the regulatory heme transcription factors, BTB Domain And CNC Homolog 1 (BACH1) expression is closely associated with IVDD. In vivo experiments confirmed that knockdown of BACH1 could increase GPX4 and SLC7A11 expression in IVDD, thereby inhibiting ferroptosis (Yao et al., 2023). Sirtuin 3 (Sirt3) is a critical regulator of ROS. High expression of ubiquitin-specific protease 11 (USP11) alleviates ferroptosis caused by oxidative stress. Sirt3 has been found to increase oxidative stress and induce ferroptosis to promote IVDD, while USP11 can bind to Sirt3 and stabilize Sirt3 to slow IVDD progression (Zhu et al., 2023a).

Epigenetics also regulates ferroptosis in IVDD. MiR-10A-5p mediated overexpression of IL-6R in disc cartilage is responsible for ferroptosis in IVDD (Bin et al., 2021). Circ0072464 downregulation and miR-431 upregulation were observed in IVDD, and this result triggered high NRF2 expression, thereby promoting NP proliferation to alleviate IVDD and improve prognosis (Yu et al., 2022). MiR-672-3p promotes ferroptosis during spinal cord injury by downregulating ferroptosis suppressor protein 1 (FSP1) (Wang F. et al., 2022). As a competitive RNA for miR-5627-5p, lncGm36569 induced upregulation of FSP1 to alleviate ferroptosis.

Cartilage damage is a cardinal feature of OA. As mentioned above, cartilage damage is caused by nothing more than abnormal ROS production and iron metabolism. Regulation of iron metabolism can affect chondrocyte survival. Iron chelators are drugs that are effective against diseases caused by iron accumulation. Iron load is a marker of ferroptosis, so rational use of iron chelators is an effective treatment to cope with ferroptosis. For clinical application, three iron chelators—Deferoxamine (DFO), deferasirox (DFX), and deferiprone (DFP)—have been approved (Mobarra et al., 2016). DFO is an iron chelator approved by the US Food and Drug Administration. DFO was shown to prevent IL-1β-induced upregulation of matrix metallopeptidase 13 (MMP13), and this result also indirectly confirmed that iron is involved in chondrocyte apoptosis in OA (Jing et al., 2020). DFO can also reverse MMP13 activation triggered by erastin, an ferroptosis inducer, and reduce protection against chondrocyte injury by promoting NRF2 pathway activation (Guo et al., 2022). In addition, after DFO treatment, cartilage under hypoxia showed higher ultimate tensile strength and pyridinoline (a collagen protein of mature articular cartilage), although the aim of this finding was to evaluate the mechanical properties of new cartilage, it can also be seen from the results that regulating iron content has far-reaching significance for cartilage tissue (Otarola et al., 2022). In a mouse model, it was found that by intra-articular injection of ferrostatin-1 (an ferroptosis inhibitor), the NRF2 system is activated, attenuating IL-1β-induced ROS accumulation and relieving chondrocyte breakdown, which is a new way to treat OA (250). Another animal experiment also demonstrated that mitochondrial morphology was restored in chondrocytes undergoing ferroptosis after joint injection of ferrostatin-1 and astaxanthin, and collagen II was upregulated due to attenuation of IL-1β (Wang et al., 2022e). Hypoxic environment impacts the body in a complex state, as mentioned above. Several recent studies have focused on the key role of HIF in OA progression (Gonzalez et al., 2018). D-mannose, an isomer of glucose, has been reported to inhibit LPS-induced IL-1β production, which is considered an effective treatment for OA (Torretta et al., 2020). Recent studies have confirmed that D-mannose can inhibit HIF-1α-mediated ferroptosis in chondrocytes (Zhou et al., 2012). HIF-2α is also a non-negligible factor in OA progression. Relevant studies have confirmed that HIF-2α can lead to cartilage destruction by affecting the expression of genes responsible for metabolism in chondrocytes (Saito et al., 2010; Yang et al., 2010; Yang et al., 2015). D-mannose can inhibit HIF-2α to reduce the sensitivity of chondrocytes to ferroptosis (Zhou et al., 2021). Moreover, D-mannose inhibited OA degeneration brought on by IL-1β in rat chondrocytes by triggering autophagy via the AMPK pathway (Lin Z. et al., 2021). Some medicinal ingredients from traditional Chinese medicine are also widely used to treat OA. Icariin, the main component of herb Epimedium, has been demonstrated to reduce the expression of IL-1β, MMP, and GRP78, and its mechanism of action is to activate the System X_c ⁻/GPX4 pathway to inhibit ferroptosis (Luo and Zhang, 2021; Pan et al., 2017). Stigmasterol, the main component of Achyranthes bidentata, also acts on IL-1β to reduce its chondrocyte damage and regulates ferroptosis through sterol regulatory elements combined with transcription factor 2 (Mo et al., 2021). Intra-articular injection of Cardamonin, one of the extracts of ginger, also inhibited IL-1β-mediated cartilage explanation and regulated ferroptosis through the p53 pathway (Gong et al., 2023).

There are few reports on the treatment of AS in ferroptosis, but a number of studies have dominated the prediction of ferroptosis genes closely related to AS. With these predicted genes as primary target points, therapeutic strategies for AS can be identified. Li et al. constructed a protein network of ferroptosis and AS and collected gene expression profiles of AS patients through the GEO database, and concluded that DNA Damage Inducible Transcript 3 and Heat Shock Protein Family B (Small) Member 1 are target genes for inducing ferroptosis in AS cells after enrichment analysis (Li Q. et al., 2022). Another analysis identified Small Ubiquitin Like Modifier 2 and NADH:Ubiquinone Oxidoreductase Subunit S4 as hub genes for ferroptosis in AS cells by constructing differential gene and protein networks (Rong et al., 2022). Dong et al. screened Chloride Intracellular Channel 4 and Tripartite Motif Containing 21 (TRIM21) as key genes in ferroptosis-regulated AS by using a disease prediction model for differential genes involved in cell death, with TRIM21 expression elevated in male patients (Dong et al., 2024). It has been established that acrylamide raises the risk of AS. Several cancers are caused by aflatoxin, which is produced when food is heated. Additionally, it can raise the risk of AS by causing autophagy-dependent ferroptosis. It is therefore advised to limit the sources of acrylamide in meals (Wang H. et al., 2023).

Inflammation and ROS are key factors in the pathogenesis of GA and the mechanism of ferroptosis. Targeting ROS-NLRP3 for GA is the primary strategy. Multiple ROS-NLRP3 blockers have been demonstrated to treat GA (Zhang et al., 2024). Multiple natural medicines have proven effective in treating GA. Carvacrol blocked ROS-NLRP3-mediated inflammation, decreased oxidative stress, and decreased uric acid levels in GA patients (Riaz et al., 2022). The natural flavonoid compound rutin was demonstrated to inhibit ROS production and inhibit ROS-NLRP3 inflammatory activation thereby improving joint swelling in a quail GA model (Wu H. et al., 2023). The non-coding RNA lncRNA ZNF883 is one of the key genes identified as ferroptosis leading to GA (Shao et al., 2024). Targeting lncRNA Zinc Finger Protein 883 to treat GA is therefore a drug worth investigating. Targeted modulation of XO is another way. DEP Domain Containing 5 (DEPDC5) subunit deficiency can lead to increased XO and ROS accumulation, which leads to ferroptosis (Li S. et al., 2024). Targeting DEPDC5 pharmaceuticals may be one way to treat GA. Drugs observed from models in which non-ferroptosis leads to GA also decrease XO levels, suggesting that these are potential agents for the treatment of GA. Artemisia argyi essential oil could decrease XO and upregulate GPX4 in the hepatic ferroptosis model induced by bisphenol A (Cui et al., 2023). Empagliflozin, a selective inhibitor of sodium-glucose cotransporter 2, alleviated doxorubicin-induced myocardial ferroptosis and decreased XO expression (Quagliariello et al., 2021). The results of transcriptomic and metabolomic analysis showed that exposure to PM2. Five environment reduced antioxidant capacity, increased XO expression, and ultimately led to ferroptosis in mice. Avoiding PM2. Five is therefore also one of the ways to prevent GA resulting from ferroptosis (Shi et al., 2022).

Inhibition of synovial hyperplasia to restore synovial homeostasis is an effective treatment for RA (Sandhu and Thelma, 2022). Antioxidant dysregulation due to FLS is a risk factor for RA. Promoting ferroptosis in FLS has therefore emerged as a way to treat RA. Imidazolone erastin (IKE) and the TNF antagonist etanercept induced ferroptosis in FLS and reduced RA symptoms (Wu et al., 2022). Glycine can promote FLS ferroptosis through S-adenosylmethionine mediated methylation of the GPX4 promoter (Ling et al., 2022). Asiatic acid can die from its FLS iron by increasing Fe²⁺ (Sun et al., 2024). Quercetin is a natural flavonoid, and cells treated by quercetin not only showed inhibition of FLS proinflammatory ability, but also showed that caspase-8 levels, a marker of ferroptosis, could be reduced (Zheng Q. et al., 2023). In addition to natural medicines, drugs targeting FLS modulation have now been developed and proven effective. Cathepsin B is a protease involved in joint injury and is highly expressed in articular cartilage in RA. Its inhibitor CA-074Me inhibited FLS proliferation and promoted FLS ferroptosis (Luo et al., 2024). Sulfasalazine, as a treatment for AS, has been shown to promote ferroptosis in FLS in RA (Zhao et al., 2024). Several differential gene analyses yielded genes involved in regulating ferroptosis in FLS. Several differential gene analyses yielded genes involved in regulating ferroptosis in FLS. Wang et al. analyzed eight ferroptosis genes associated with RA, of which TIMP Metallopeptidase Inhibitor 1 was significantly expressed in FLS (Wang et al., 2024b). Jing et al. identified SLC2A3 as highly expressed in FLS by bioinformatics methods and machine learning algorithms and experimentally verified that FLS treated with RSL3 exhibited SLC2A3 downregulation and underwent ferroptosis (Xiang et al., 2023). Therefore, it is well documented to treat differential genes. Nuclear Receptor Coactivator 4 (NCOA4) mediates LPS-induced ferroptosis in FLS and targeting NCOA4 may be an effective strategy for the treatment of RA (Wang Y. et al., 2024).

In addition to targeting FLS, ways to interfere with ferroptosis for RA have also been mostly reported. An injectable gel composed of folic acid-functionalized polydopamine and leonurine (Leon) inhibits joint inflammation caused by macrophages and protects cartilage from ferroptosis (Lv et al., 2024). It is a novel way to treat RA by carrying Fe₃O₄ and sulfasalazine by using macrophages as carriers (Ruan et al., 2024). In this experiment, macrophage carriers could be transported to sites of RA inflammation guided by inflammatory factors and under near-infrared light irradiation, Fe₃O₄ converted light energy to heat energy. This synergistic effect, instead, predisposes inflammatory cells and proliferating synovium to ferroptosis, thereby achieving the effect of treating RA.

BMSCs are an important source of OBs and OCs differentiation is influenced by RANKL. When OP develops, OBs differentiation is inhibited, and OCs differentiation is enhanced. Targeting BMSCs and RANKL is therefore a way to treat OP. Ferroptosis has been mostly reported to affect BMSCs and RANKL, and OP based on ferroptosis is a hot area of current research.

As a naturally occurring phenolic chemical, Picein enhances BMSCs’ capacity for osteogenic differentiation while reducing oxidative stress caused by erastin via the Nrf2/HO-1/GPX4 pathway (Huang et al., 2024a). Overexpression of Crystallin Alpha B (CRYAB) increased OCN and Runx2 expression and increased ALP activity in BMSCs. Further experiments verified that CRYAB could interact with FTH1, inhibit ferroptosis of BMSCs, and promote osteogenic differentiation (Tian et al., 2024). BMSCs induced by high glucose and high fat environments exhibited bone degradation and ferroptosis, but this was reversed by poliumoside. When poliumoside was used in the T2DOP mouse model, increased bone mineral density and GPX4 expression were observed in the distal femur of mice, which also confirmed its effectiveness with cellular experiments (Xu et al., 2024). Based on a DNA tetrahedral nanoparticle involved in curcumin, tFNA-Cur, could inhibit ferroptosis in BMSCs and promote osteogenic differentiation in diabetic environment through Nrf2/GPX4 pathway (Li et al., 2024d). Ebselen is a selenium-containing organic drug molecule that can act as a mimetic of GPX. The experiment verified that Ebselen improved the ferroptosis and osteogenic differentiation inhibition status of BMSCs induced by LPS (Huang Z. et al., 2023). Engeletin, as an endogenous antioxidant, can promote osteogenic differentiation of BMSCs and upregulate osteogenesis-related proteins, which has achieved the effect of counteracting ferroptosis (Huang L. et al., 2023). Tocopherol as an antioxidant can reduce oxidative stress in BMSCs, promote osteogenesis-related protein expression, and inhibit ferroptosis in BMSCs (Lan et al., 2022b). Vitamin K2 has been used clinically to prevent OP. In cell experiments, vitamin K2 reversed ferroptosis and upregulated osteogenic marker expression in BMSCs under high glucose conditions (Jin et al., 2023).

In addition, novel medical devices have been developed to target the inhibition of osteogenic differentiation caused by ferroptosis. Targeted regulation of BMSCs metabolic status is a critical point to promote osteoblast differentiation. Therapeutic protocols targeting BMSCs metabolism were therefore designed and experimentally confirmed. Yang designed a titanium implant coated with caffeic acid and DFO. Titanium implants were implanted into the femoral epiphysis of OVX rats, and it was observed that titanium implants promoted new bone formation after 1 month. Its mechanism of action is to reduce the lipid peroxidation level of BMSCs by activating the KEAP1/NRF2/HMOX1 pathway and to activate and promote the SLC7A11/GSH/GPX4 axis to inhibit BMSCs ferroptosis (Yang Y. et al., 2024). Bone cement is commonly used to treat OP fractures. However, its cytotoxic properties make it likely to have an impact on osteogenic differentiation. A composite PDT-TCP-SE based on polylactide-based copolymer (PDT), β-tricalcium phosphate (β-TCP), and selenium nanoparticles (SeNPs) was developed to replace the application of traditional bone cements. It was found that PDT-TCP-SE could protect BMSCs from erastin-induced ferroptosis through Sirt1/Nrf2/GPX4 antioxidant pathway and had the effect of regulating new osteogenesis at OP fracture site (Huang et al., 2024b).

Saikosaponin A, a component of the natural medicine Bupleurum falcatum, can inhibit RANKL-induced OCs production and inhibit the Nrf2/SCL7A11/GPX4 axis to promote ferroptosis in OCs (Li TQ. et al., 2024). Zoledronic acid is a bisphosphonate that blocks ferrostatin-1 ‘s ability to induce osteoclast death. Moreover, the expression of ferroptosis-related expression in OCs treated with zoledronic acid was significantly increased, and these results indicated that zoledronic acid could puncture osteoclast ferroptosis (Qu et al., 2021). Further studies with zoledronic acid have found that it is through inhibition of the RANKL signaling pathway that OCs production is inhibited and bone loss is relieved (Wang B. et al., 2022). Artemisinin has been shown to downregulate RANKL-induced differentiation of OCs and has been used in place of treating bone loss caused by OCs. Because of the high iron content in OCs, the mechanism of action of artemisinin was identified as possibly associated with ferroptosis (Zhang, 2020).

Osteocyte metabolism affects OP caused by ferroptosis is rarely reported, however, as the most abundant cells in bone, regulating osteocyte metabolism is undoubtedly a worthwhile attempt. Activation of Activating Transcription Factor 2 (ATF2) has been found to induce ferroptosis in osteocytes, a phenomenon that is inextricably linked to age-related bone loss. AFT2 expression was suppressed and OP progression was slowed by administration of JY-2, a novel Forkhead Box O1 inhibitor (Yin et al., 2024). Eldecalcitol is an orally active vitamin D analogue (Sanford and McCormack, 2011). Eldecalcitol showed protection against bone in OVX mice induced by D-galactose. Further cell experiments confirmed that Eldecalcitol alleviated D-galactose-triggered ferroptosis, inhibited lipid peroxide accumulation, and enhanced GPX4 expression in MLO-Y4 cells (Fu et al., 2024).

In conclusion, ferroptosis can accelerate OP progression by affecting the osteogenic differentiation of BMSCs, target inhibition of ferroptosis in BMSCs, or promote ferroptosis in OCs induced by RANKL, which is a strategy worth applying for the treatment of OP.

The treatment regimen of OS is consistent with conventional cancer treatment, that is, surgery, radiotherapy, chemotherapy and other modalities. However, due to its high incidence of lung metastasis, drug resistance and other characteristics, resulting in OS treatment effect is unsatisfactory. Induction of ferroptosis in tumor cells is currently the focus of treatment options, which also brings new perspectives for the treatment of OS. Multiple agents giving mechanisms of ferroptosis have been demonstrated to inhibit OS progression. EF24, an analog of curcumin, induced osteosarcoma cell death, the outcome of which was reversed by ferrostatin-1. In-depth studies have confirmed that it can increase MDA levels, ROS levels and increase intracellular iron content. HMOX1 expression was upregulated in a dose-dependent manner and promoted ferroptosis in osteosarcoma (Lin H. et al., 2021). The combination of ursolic acid and cisplatin induced intracellular overload of Fe³⁺, resulting in ferroptosis in osteosarcoma cells (Tang et al., 2021). Tipazamine can inhibit the expression of GPX4 and SLC7A11 under hypoxia and thus induce ferroptosis (Shi et al., 2021). Sulfasalazine and miR-1287-5p mimics could inhibit GPX4 to promote ferroptosis in osteosarcoma cells (Xu Z. et al., 2021; Liu J. et al., 2022). Bavachin, as a flavonoid compound, can promote ferroptosis in osteosarcoma cells by up-regulating p53, and down-regulating SLC7A11 and GPX4 (Luo et al., 2021). Several novel nanomedicines also exert a role in promoting ferroptosis in OS cells (Fu et al., 2021; Wang Y. et al., 2022). Ferroptosis is also involved in reducing drug resistance in osteosarcoma. miR-1287-5p rendered osteosarcoma cells more sensitive to cisplatin (Xu Z. et al., 2021). The same result was found in osteosarcoma cells after inhibition of Lysine Demethylase 4A expression (Chen M. et al., 2021). Combination of erastin, RSL3 and STAT3 inhibitors also increased sensitivity to cisplatin (Liu and Wang, 2019).

NP cell reduction or death is the main cause of IVDD. Several studies have now been directed at inhibiting NP ferroptosis to maintain its normal physiological state. Shu et al. determined that Tinoridine could rescue RSL3-induced ferroptosis in NP cells by increasing Nrf2 expression by screening nonsteroidal anti-inflammatory drugs (Yang S. et al., 2024). Fisetin is involved in the regulation of the Nrf2/HO-1 pathway, thereby inhibiting NP ferroptosis (Li C. et al., 2024). Hesperidin can enhance Nrf2 expression and inhibit NF-κB, thereby alleviating ferroptosis resulting from oxidative stress in NP (Zhu et al., 2023b). HIF-1α promotes translation of SLC7A11 and reduces NP ferroptosis under hypoxia by inducing expression of the m6A reading protein YTHDF1 (Lu et al., 2024). DNA methyltransferase inhibitors prevented puncture-induced IVDD and protected NP from ferroptosis (Chen J. et al., 2024). In vivo experiments confirmed that targeting the miR-874-3p/ATF3 axis could modulate NP ferroptosis and is an effective way to treat IVDD (Wang X. et al., 2024). Circ-STC2 is a critical circRNAs involved in IVDD (Chang et al., 2021). In cell experiments against Circ-STC2, Circ-STC2 was found to be highly expressed in IVDD tissues. Knockdown of Circ-STC2 promoted NP cell viability and prevented from suffering ferroptosis (Xiong et al., 2023). A hydrogel containing SLC7A11-modRNA inhibited ferroptosis in NP cells by local injection, and the rate of SLC7A11-modRNA release positively correlated with IVDD severity (Gao et al., 2024).