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Frontiers in Musculoskeletal Disorders ·

Volume 4 - 2026 | https://doi.org/10.3389/fmscd.2026.1788598

Oxidative stress in steroid-induced necrosis of femoral head: a review revealing new insights into pathogenic mechanisms

  • Yuansheng Wu1
  • Ruixuan Ma2
  • Hongjiang Jiang1*corresponding author
  1. 1Department of Joint Surgery, Wendeng Orthopedic Hospital of Shandong Province, Weihai, Shandong, China
  2. 2Department of Nephrology, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
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Abstract

Steroid-Induced Necrosis of the Femoral Head (SINFH) has a complex pathogenesis. Disorders of bone metabolism, vascular injury, apoptosis, inflammatory responses, lipid metabolism disturbances, and oxidative stress are all closely related to the occurrence of this condition. Oxidative stress has a broad impact on various physiological functions in the body. Studies have shown that oxidative stress can affect bone metabolic balance, inflammatory responses, vascular injury, and apoptosis, thereby accelerating the progression of SINFH. Therefore, oxidative stress is crucial for the occurrence and development of SINFH. Inhibiting oxidative stress has positive implications for the treatment of steroid-induced avascular necrosis. Different classes of antioxidants exhibit distinct mechanisms of action and therapeutic potential: (1) direct free radical scavengers (e.g., vitamin C, vitamin E) primarily neutralize existing reactive oxygen species (ROS); (2) enzyme modulators (e.g., N-acetylcysteine) enhance endogenous antioxidant systems; (3) natural compounds (e.g., resveratrol, curcumin) activate nuclear factor erythroid 2-related factor 2 (Nrf2) and other signaling pathways. Their application scenarios vary accordingly, with some more suitable for prevention and others for intervention. However, maintaining a dynamic balance between oxidation and antioxidation may be more important than completely suppressing redox reactions.

Keywords

1 Introduction

Steroid-Induced Necrosis of the Femoral Head (SINFH) is caused by long-term use of glucocorticoids and other causes of abnormal bone metabolism, lipid metabolism imbalance and blood microcirculation disorders in the femoral head, resulting in bone trabecular fracture, bone tissue necrosis collapse, and hip dysfunction (1). Epidemiological surveys indicate that SINFH accounts for approximately 25% to 50% of all osteonecrosis of the femoral head (ONFH) cases (2). The exact pathogenesis of SINFH is not yet clear. However, bone metabolism disorders, vascular endothelial injury, cell apoptosis, inflammatory, and lipid metabolism disorders are considered to be the main pathological manifestations of SINFH. Oxidative stress is closely related to these pathological changes (3). Therefore, regulating oxidative stress may have significant implications for SINFH prevention and treatment (Figure 1).

Glucocorticoids(GCs) cause oxidative stress, leading to an increase in the release of ROS. ROS results in vascular injury, inflammatory response, cell apoptosis, and bone metabolic imbalance, thereby causing SINFH. The arrows indicate increased levels or activation. GCs,glucocorticoids; ROS,reactive oxygen species; SINFH,SteroiD–Induced Necrosis of the Femoral Head. (Original figure created by the authors).
Figure 1. Glucocorticoids(GCs) cause oxidative stress, leading to an increase in the release of ROS. ROS results in vascular injury, inflammatory response, cell apoptosis, and bone metabolic imbalance, thereby causing SINFH. The arrows indicate increased levels or activation. GCs,glucocorticoids; ROS,reactive oxygen species; SINFH,SteroiD–Induced Necrosis of the Femoral Head. (Original figure created by the authors).

Oxidative stress occurs due to the imbalance of endogenous antioxidant defense mechanisms. This leads to mitochondrial damage, which in turn releases reactive oxygen species (ROS) (4). Under physiological conditions, ROS can regulate cellular homeostasis and mediate intracellular signals. It is essential for the regulation of cell proliferation, survival, metabolism, apoptosis, differentiation, and migration. An excess of ROS disrupts the intracellular oxidative-reductive balance, leading to mitochondrial DNA mutations and causing irreversible cell damage. This in turn triggers a series of adverse biological effects, including bone metabolism disorders, vascular endothelial injury, and cell apoptosis (5). Research has shown that oxidative stress is abnormal in patients with SINFH and in animal models (6).

Glutathione (GSH) serves as a ROS scavenger, while malondialdehyde (MDA) represents a primary aldehyde produced by tissue lipid peroxidation. An increase in MDA levels and a decrease in GSH levels are important indicators of oxidative damage (7). In patients with non-traumatic necrosis of the femoral head, the levels of MDA in the serum increase, and the levels of Superoxide Dismutase (SOD) decrease. Furthermore, MDA levels show a positive correlation with Ficat staging, while SOD levels show a negative correlation (8). NADPH Oxidases (NOX) are important sources of ROS in cells. A study by Zhang et al. (9) found that the expression of NOX1, NOX2, and NOX4 proteins in rats with SINFH significantly increased. Drugs with antioxidant effects, such as thymoquinone, Vitamin C, and Vitamin E (10), can increase the levels of GSH in the serum, reduce the levels of MDA, and delay the development of SINFH.

Unlike previous reviews that have focused on individual aspects of oxidative stress in SINFH, this review provides several novel contributions: (1) a systematic analysis of the dual role of reactive oxygen species (ROS), distinguishing between physiological signaling functions and pathological oxidative damage; (2) an integrated examination of the crosstalk between oxidative stress and other pathological processes, including bone metabolism disorders, vascular injury, apoptosis, inflammation, and—newly incorporated in this review—lipid metabolism disorders; (3) a comparative evaluation of multiple signaling pathways (Nrf2/Keap1, Wnt/β-catenin, Akt, JNK/c-Jun) with assessment of their relative importance, upstream/downstream relationships, and therapeutic potential; and (4) a critical discussion of research gaps and clinical translation challenges that identifies specific bottlenecks in developing antioxidant-based therapies for SINFH. It is hoped that this will provide some reference for the clinical and basic research of SINFH.

2 The dual role of ROS in SINFH

2.1 Mechanisms of oxidative stress

Under physiological conditions, ROS can regulate cellular homeostasis and mediate intracellular signaling, making them essential for the regulation of cell proliferation, survival, metabolism, apoptosis, differentiation, and migration (11). However, excessive ROS may lead to metabolic dysfunction. The main sources of ROS in cells are NOX enzymes and mitochondria (12). NOX enzymes are important enzymes involved in intracellular redox reactions. They catalyze the reaction between nicotinamide adenine dinucleotide phosphate (NADPH) and oxygen, generating superoxide anions (O2−) (13, 14), Figure 2. The mechanism of NOX enzymes involves transferring electrons from NADPH to molecular oxygen, producing O2−, which can further be converted into hydrogen peroxide (H2O2), a strong oxidizing agent (15). In mitochondria, ROS are formed during oxidative phosphorylation by oxidizing reduced nicotinamide adenine dinucleotide (NADH) to NAD. The superoxide anions produced by mitochondria and NOX2 are quickly converted into H2O2 by an enzyme called superoxide dismutase (16). Hydrogen peroxide is a potent oxidant, and antioxidant proteins in the cell (peroxiredoxins, catalase, GSH) reduce H2O2 to water, thereby maintaining ROS stability (17, 18). Moderate ROS help eliminate damaged cells or foreign substances by regulating apoptosis or autophagy pathways, maintaining tissue health and stability (19). However, excessive oxidative stress can lead to the overactivation of programmed cell death, triggering tissue damage and loss of function (20).

Doxorubicin (DOX) upregulates NOX2 and NOX4 expression by activating the angiotensin receptor, oxidizes NADPH, and reduces O<sub>2</sub> to produce ROS. On the one hand, ROS causes oxidative stress and DNA damage, further activates MAPK-mediated apoptosi. On the other hand, ROS activates Drp1, inducing mitochondrial division, causing NLRP3-mediated apoptosis and eventually causing myocardial damage. Natural compounds including neferine **(N)**, valsartan **(V)**, necrostain-1 (N-1), setanaxib **(S)**, astragaloside (AS), acacia **(A)**, irisin **(I)**, NSC23766 (NS) and resolvin D1 **(R)** attenuated DOX-induced cardiomyopathy by downregulation of NOX2 and NOX4 (14). Solid black arrows indicate direct activation or conversion pathways. DOX,doxorubicin; NOX2/4,NADPH Oxidase 2 and 4; NADPH,nicotinamide adenine dinucleotide phosphate; ROS,reactive oxygen species; MAPK,mitogeN,Activated protein kinase; Drp1,dynamiN–Related protein 1; NLRP3,NOD–Like receptor protein 3. *Copyright @ 2023, The Author(s), Published by Cell Commun Signal. Adapted with permission*.
Figure 2. Doxorubicin (DOX) upregulates NOX2 and NOX4 expression by activating the angiotensin receptor, oxidizes NADPH, and reduces O2 to produce ROS. On the one hand, ROS causes oxidative stress and DNA damage, further activates MAPK-mediated apoptosi. On the other hand, ROS activates Drp1, inducing mitochondrial division, causing NLRP3-mediated apoptosis and eventually causing myocardial damage. Natural compounds including neferine (N), valsartan (V), necrostain-1 (N-1), setanaxib (S), astragaloside (AS), acacia (A), irisin (I), NSC23766 (NS) and resolvin D1 (R) attenuated DOX-induced cardiomyopathy by downregulation of NOX2 and NOX4 (14). Solid black arrows indicate direct activation or conversion pathways. DOX,doxorubicin; NOX2/4,NADPH Oxidase 2 and 4; NADPH,nicotinamide adenine dinucleotide phosphate; ROS,reactive oxygen species; MAPK,mitogeN,Activated protein kinase; Drp1,dynamiN–Related protein 1; NLRP3,NOD–Like receptor protein 3. Copyright @ 2023, The Author(s), Published by Cell Commun Signal. Adapted with permission.

Excessive ROS production can lead to the development of diseases such as obesity, insulin resistance, hyperglycemia, chronic inflammation, and dyslipidemia (21–23). For example, ROS-induced oxidation of lipids can trigger lipid peroxidation, generating lipid peroxides that further damage the integrity of cell membranes, leading to necrosis or apoptosis (24). On the other hand, ROS attack on DNA can cause gene mutations and chromosomal breaks, thereby increasing the risk of cancer, aging, and other diseases. Additionally, oxidative stress can promote chronic inflammatory responses by activating various transcription factors (such as NF-κB) and pro-inflammatory mediators, providing a biological foundation for the development of numerous diseases (25). Overall, oxidative stress is not only a direct consequence of cellular imbalance but also involves changes in multiple cellular protective mechanisms. Cells respond to excessive ROS by activating antioxidant enzyme systems, stress responses, repair mechanisms, and autophagy processes to maintain cellular homeostasis (26, 27). However, under long-term or excessive oxidative stress, the failure of the antioxidant system prevents effective ROS clearance, leading cells into an irreversible damage phase, potentially triggering apoptosis or necrosis (14, 28).

Research has shown that sustained oxidative stress plays a crucial role in bone joint diseases, particularly in SINFH. During the development of SINFH, oxidative stress not only induces cell apoptosis and DNA oxidative damage but also alters the function of endothelial cells and the proliferation and differentiation of BMSCs, further exacerbating the progression of the disease (7, 29, 30). Therefore, studying the mechanisms of oxidative stress is of significant importance in understanding the pathogenesis of SINFH.

2.2 Physiological signaling vs. oxidative stress

Reactive oxygen species (ROS) exert concentration-dependent effects on cellular function, a concept we term the “oxidative window—the optimal range of ROS required for normal physiological processes. At low to moderate concentrations, ROS function as essential second messengers that regulate multiple cellular activities. Physiological ROS, primarily generated by NADPH oxidases (NOX enzymes) in response to growth factors and cytokines, participate in the regulation of cell proliferation, survival, differentiation, migration, and metabolism (11). For instance, BMP-2 activates NOX to induce physiological ROS production, which serves as a signaling trigger for osteoblast differentiation (31). Similarly, ROS-mediated activation of ERK1/2 and p38 MAPK pathways is crucial for osteoblast proliferation and differentiation (32).

In contrast, excessive ROS production overwhelms cellular antioxidant defenses, leading to oxidative stress. Supraphysiological ROS levels cause mitochondrial DNA mutations, lipid peroxidation, protein carbonylation, and irreversible cell damage (29). This pathological state triggers a cascade of adverse effects, including bone metabolism disorders, vascular endothelial injury, and cell apoptosis (20). The transition from physiological signaling to pathological oxidative stress depends on the magnitude, duration, and subcellular location of ROS production. Therefore, the therapeutic goal in SINFH should not be complete elimination of ROS, but rather restoration of redox homeostasis within the oxidative window.

3 Mechanisms of oxidative stress associated with SINFH

3.1 Effect of oxidative stress on osteogenic differentiation

Osteoblasts are the type of cells responsible for the formation and repair of bone tissue (33). A decline in osteogenic differentiation ability is considered one of the pathological characteristics of SINFH (34). Research has found a close relationship between oxidative stress and osteogenic differentiation. ROS can not only inhibit the expression of runt-related transcription factor-2 (Runx2) and bone morphogenetic protein-2 (BMP-2), but also prolong the cell cycle, reducing the ability for osteogenic differentiation (3). Therefore, inhibiting the reduction in osteogenic differentiation activity caused by oxidative stress is one of the approaches to treating SINFH (9).

The sirtuin family members exhibit opposing roles in regulating oxidative stress and osteogenic differentiation in SINFH, highlighting the complexity of redox regulation. SIRT6 and SIRT3 function as protective factors: Fang et al. (35) found that SIRT6 knockout mice showed decreased ALP expression and reduced osteogenic differentiation of BMSCs, while promoting SIRT6 expression reduced ROS accumulation and enhanced alkaline phosphatase (ALP) activity. Similarly, Chen et al. (36) discovered that resveratrol activates the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/SIRT3 pathway, inhibiting oxidative stress in bone marrow mesenchymal stem cells (BMSCs) and enhancing Runx2 and osteocalcin (OCN) expression. In contrast, SIRT2 exerts opposing effects—it induces oxidative stress and promotes BMSC apoptosis. Inhibiting SIRT2 expression alleviates oxidative stress and cell apoptosis, slowing SINFH progression (2). This functional divergence among sirtuin family members suggests that therapeutic strategies should selectively target specific isoforms rather than broadly modulating sirtuin activity.

In summary, oxidative stress is often detrimental to osteogenic differentiation, so inhibiting oxidative stress is an important method to promote osteogenic differentiation. However, we have also found different research reports. For example, Arakaki N et al. (37) found that the antioxidant N-acetyl cysteine (NAC) can inhibit the mineralization of MC3T3-E1 cells in a dose-dependent manner, suggesting that ROS may have a positive effect on the mineralization of osteoblasts. The relationship between ROS and osteogenic differentiation is concentration-dependent. Arakaki N et al. (37) found that the antioxidant N-acetyl cysteine (NAC) inhibits mineralization of MC3T3-E1 cells in a dose-dependent manner, suggesting that physiological levels of ROS are required for osteoblast mineralization. This is supported by evidence that BMP-2 activates NOX to induce physiological ROS production, which marks the initiation of osteoblast differentiation (31). Furthermore, the ERK1/2 and p38 MAPK pathways, which are downstream effectors of ROS, play crucial roles in osteoblast proliferation and differentiation. Therefore, ROS functions as a second messenger regulating osteoblast and osteoclast activity at physiological concentrations (5), while excessive ROS produces detrimental effects. This underscores that the therapeutic objective should be maintaining ROS within the physiological range rather than complete elimination.

3.2 Effect of oxidative stress on osteoclasts

Osteoclasts originate from monocytes in the bone marrow and are primarily responsible for the absorption and decomposition of bone tissue, thereby promoting bone remodeling and repair (38, 39). Research has shown that abnormal osteoclast activity is one of the causes of ONFH (40). ROS is closely related to the activation of osteoclasts (41). Macrophage colony-stimulating factor (M-CSF) and nuclear factor κB receptor activator ligand (RANKL) are key to the differentiation of monocyte into osteoclasts. Under oxidative stress conditions, ROS leads to the overactivation of RANKL and its receptor RANK, triggering the activation of the MAPKs signaling cascade, which in turn activates nuclear factor of activated T-cells 1 (NFATC1), increasing osteoclast differentiation and enhancing bone resorption (42, 43). Therefore, inhibiting the excessive activity of osteoclasts caused by oxidative stress is an important approach to treating SINFH.

Research has found that in the necrotic area of the human femoral head, antioxidant enzymes [hydrogen peroxide enzyme, γ-glutamylcysteine synthetase (γ-GCSc), superoxide dismutase 1 (SOD1)] are significantly downregulated, while osteoclast-related proteins [cathepsin K (CTSK), tartrate-resistant acid phosphatase (TRAP)] are significantly upregulated (40). The decrease in antioxidant enzyme levels puts the femoral head in a state of high oxidative stress, thereby accelerating the recruitment and activation of osteoclasts, ultimately leading to excessive osteoclast activity and accelerating the development of ONFH. Therefore, restoring the balance of oxidation/antioxidation is key to inhibiting the activation of osteoclasts. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in regulating intracellular oxidative stress and antioxidation. It can inhibit excessive bone resorption caused by oxidative stress by regulating the binding of RANKL and its receptor (44), Figure 3. Xu et al. found that Tanshinone I, the main active ingredient of Danshen, can increase the activity of antioxidant enzymes by activating the Nrf2 signal, thereby inhibiting the excessive activation of osteoclasts caused by ROS (45).

Potential mechanisms by which NRF2 inhibits osteoclast differentiation. RANKL-induced ROS production and several other signaling pathways are crucial to osteoclast formation. By regulating the production of ROS and the expression levels of NF-κB, MAPKs, AP-1 as well as mitochondrial generation and other related signaling pathways, the NRF2/ARE signaling pathway ultimately inhibits the activity of NFATC1, a key transcription factor for osteoclast differentiation, thereby inhibiting osteoclast differentiation. (Dotted blue arrows indicate molecular displacement; the solid blue arrow indicates the subsequent effect; the red “T” line indicates inhibition) (44). NRF2, Nuclear Factor Erythroid 2-Related Factor 2; ARE, Antioxidant Response Element; RANKL, Receptor Activator of Nuclear Factor κB Ligand; RANK, Receptor Activator of Nuclear Factor κB; ROS, reactive oxygen species; NF-κB, Nuclear Factor κB; MAPKs, Mitogen-Activated Protein Kinases; AP-1, Activator Protein 1; NFATC1, Nuclear Factor of Activated T-cells 1. Copyright *©2022 The Authors. Published by Front Endocrinol (Lausanne).* Adapted with permission.
Figure 3. Potential mechanisms by which NRF2 inhibits osteoclast differentiation. RANKL-induced ROS production and several other signaling pathways are crucial to osteoclast formation. By regulating the production of ROS and the expression levels of NF-κB, MAPKs, AP-1 as well as mitochondrial generation and other related signaling pathways, the NRF2/ARE signaling pathway ultimately inhibits the activity of NFATC1, a key transcription factor for osteoclast differentiation, thereby inhibiting osteoclast differentiation. (Dotted blue arrows indicate molecular displacement; the solid blue arrow indicates the subsequent effect; the red “T” line indicates inhibition) (44). NRF2, Nuclear Factor Erythroid 2-Related Factor 2; ARE, Antioxidant Response Element; RANKL, Receptor Activator of Nuclear Factor κB Ligand; RANK, Receptor Activator of Nuclear Factor κB; ROS, reactive oxygen species; NF-κB, Nuclear Factor κB; MAPKs, Mitogen-Activated Protein Kinases; AP-1, Activator Protein 1; NFATC1, Nuclear Factor of Activated T-cells 1. Copyright ©2022 The Authors. Published by Front Endocrinol (Lausanne). Adapted with permission.

Abnormal osteoclast activity can lead to the loss of structural integrity of the femoral head and subchondral bone fractures, thereby accelerating the development of ONFH (46). Oxidative stress plays a significant role in the excessive activation of osteoclasts, especially under the induction of steroids, where oxidative stress is more prominent. Therefore, inhibiting oxidative stress to suppress the excessive activation of osteoclasts and improve bone metabolic imbalance is a potential strategy for treating SINFH

3.3 Effect of oxidative stress on apoptosis

Apoptosis is a form of programmed cell death that is closely related to the occurrence of ONFH (47). Especially under the induction of hormones, apoptosis accelerates, the death of cells inside the femoral head increases, leading to damage to the normal structure and function of the skeleton (29). Glucocorticoids (GCs) can cause oxidative stress in bone cells. ROS leads to an increase in endoplasmic reticulum stress, which in turn causes mitochondrial DNA (mtDNA) damage, ultimately activating the B-cell lymphoma 2 (Bcl-2)/BAX apoptosis pathway, leading to cell apoptosis (48, 49). Therefore, inhibiting cell apoptosis caused by oxidative stress is of great significance for the treatment of SINFH.

In SINFH, many oxidative stress signal markers show significant abnormalities. For example, 8-hydroxy-2′-deoxyguanosine (8-OHdG) is a major marker of DNA oxidative damage. Zhang et al. (9) found that the expression level of 8-OHdG in SINFH patients is positively correlated with bone cell apoptosis; antioxidants diphenyleneiodonium (DPI) and N-acetylcysteine (NAC) can reduce 8-OHdG and oxidative stress levels, reversing Dex-mediated bone cell apoptosis. The Nrf2 signaling pathway plays a crucial role in oxidative stress-mediated cell apoptosis. After free Nrf2 enters the cell nucleus, it activates the expression of antioxidant enzymes such as manganese superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPx), thereby protecting BMSCs from oxidative stress-induced cell apoptosis (30). Studies have shown that antioxidants such as parkinson's protein 7 (PARK7) (50), monoacylglycerol lipase (MAGL) inhibitors (49), taxifolin (51), and astaxanthin (52) can all activate the Keap1/Nrf2 pathway to resist oxidative stress-induced cell apoptosis. The Caspase family is the core mechanism of cell apoptosis, which can cleave cell structures and inhibit DNA repair (53). Activation of caspase-3 affects DNA replication and transcription, and disrupts DNA repair (54). In normal bone cells, Bcl-2 inhibits cell apoptosis by blocking the transmission of apoptotic signals. Jia et al. (55) found that in SINFH animal models, Bcl-2 expression decreased and caspase-3 expression increased; Vitamin E can reduce the expression of caspase-3, up-regulate the expression of Bcl-2, alleviate DNA oxidative damage of bone marrow hematopoietic cells, and inhibit cell apoptosis. NOX is an important source of ROS in cells. Bai S C (56) found that the expression of NOX1, NOX2, and NOX4 in cells is dose-dependent with osteoblast apoptosis, and antioxidants NAC, DPI, and siRNA-NOX can reverse oxidative stress-induced osteoblast apoptosis.

In summary, cell apoptosis is one of the important causes of SINFN occurrence and subsequent femoral head collapse, and there is often a positive correlation between oxidative stress and cell apoptosis. Therefore, inhibiting oxidative stress-mediated cell apoptosis is one of the strategies for treating SINFH.

3.4 Effect of oxidative stress on vascular injury

Bone microvessels, as an important part of the bone microenvironment, play a crucial role in the nutrition metabolism and endocrine of bone cells (57). Microcirculation dysfunction can lead to bone metabolism, nutrient transport, and bone microenvironment abnormalities (58). There is a close relationship between oxidative stress and bone microvascular injury (59). Research has found that oxidative stress causes structural and functional impairments of vascular endothelial cells, increases the risk of thrombosis formation, and exacerbates the degree of ischemia and hypoxia in the femoral head (60). Particularly under glucocorticoid stimulation, the GSH level required to maintain the body's redox state decreases, and related lipid metabolism abnormalities can induce oxidative stress, leading to vascular endothelial cell oxidative stress, increased vascular permeability, and ultimately contributing to SINFH development (61).

Functional microvascular injury or capillary sparseness is considered a potential mechanism of SINFH. Li et al. (62) found that two weeks after steroid injection, the perfusion frequency of small vessels in the femoral head of rats was significantly reduced, and the perfusion frequency of large vessels was significantly increased. In addition, extensive oxidative damage was found in the bone marrow vessels, and the antioxidant edaravone could significantly reduce steroid-induced oxidative damage, increase small vessel perfusion, and reduce intravascular thrombosis. In addition to changes in vascular perfusion frequency, oxidative stress also affects the vasculature by altering vascular permeability. Ichisek (63) found that in rabbits, vascular permeability increased 3–5 days after steroid administration. GSH can reduce the accumulation of lipid peroxidation (LPO) and advanced glycation end products (AGE), thereby reducing the incidence of SINFH. In addition to changes in vascular permeability in SINFH, there are also changes in vascular density. Dasci et al. (64) found that Thymoquinone can reduce the levels of MDA, increase the levels of GSH, and alleviate oxidative stress-induced vascular endothelial injury. Moreover, hydrogen-rich saline has been reported to increase GSH levels and microvascular density in the femoral head in an experimental rabbit model; however, this finding is based on a single study and requires further validation through large-sample studies and clinical trials (65). Vascular lesions are considered the initial pathological changes in ONFH. Microvascular lesions lead to blood circulation disorders and ischemia-hypoxia in bone tissue, which in turn trigger a series of more severe pathological changes such as inflammatory responses, cell apoptosis, and bone tissue repair and reconstruction. Therefore, the principle of early detection and intervention for bone microvascular lesions should be adhered to, and one of the methods is to prevent the occurrence of oxidative stress.

3.5 Effect of oxidative stress on inflammatory

From an osteoimmunology perspective, ONFH is considered a complex bone immune disorder, characterized essentially by persistent chronic inflammation (66, 67). Studies have found that in the peripheral blood and bone tissue of ONFH patients, the expression of M1 pro-inflammatory macrophages, Th17 cells, and pro-inflammatory cytokines such as TNF-α and IL-17 are elevated (68). There is a close relationship between the inflammatory response and oxidative stress. Oxidative stress leads to the accumulation of ROS, and excessive ROS induce cell apoptosis and increase the release of pro-inflammatory cytokines (69). These factors not only cause osteoclasts to be overly active but also lead to changes in the local immune microenvironment (70). Therefore, inhibiting the inflammatory response caused by oxidative stress is particularly important for maintaining the stability of the bone immune microenvironment (58, 71).

The natural polyphenol antioxidant catechol quinone (CQ) can continuously inhibit free radicals to prevent the activation of inflammation. Kim et al. (72) sprayed CQ onto the surface of antioxidant-coated whitlockite bone scaffolds, and then implanted them into the bone defect site after core decompression (CD) surgery. The results showed that the antioxidant-coated whitlockite bone scaffold not only reduced the levels of ROS but also decreased the release of pro-inflammatory cytokines such as IL-1β and TNF-α. Selenium (Se) is an essential trace element in the human body and an important component of antioxidants (73). After injecting Se-containing nanocomposites (Se@SiO2) into the rat peritoneal cavity, the ROS levels in the serum significantly decreased 24 h later. In addition, pre-stimulation with Se@SiO2 significantly reduced the expression levels of IL-1β and IL-6 (74). There are many similar studies, such as Coenzyme Q10, grape seed proanthocyanidins, and moringa polysaccharides (75), which have shown good performance in inhibiting oxidative stress and anti-inflammatory effects.

3.6 Effect of oxidative stress on lipid metabolism disorders

Glucocorticoids (GCs) profoundly affect lipid metabolism by promoting adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) at the expense of osteogenic differentiation (76). This results in intraosseous lipid accumulation, adipocyte hypertrophy, and increased marrow fat content, which mechanically compresses sinusoids and impairs microcirculation.

The accumulated lipids serve as substrates for lipid peroxidation, a process greatly amplified under oxidative stress conditions. ROS, particularly hydroxyl radicals, attack polyunsaturated fatty acids in cell membranes and intracellular lipid droplets, generating lipid peroxides such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) (77). These lipid peroxidation products are not merely passive markers of oxidative damage but active mediators that further exacerbate pathology: (1) they form covalent adducts with proteins, impairing enzyme function; (2) they induce mitochondrial dysfunction, promoting further ROS production; and (3) they activate inflammatory signaling pathways (24).

Conversely, lipid metabolism abnormalities can directly trigger oxidative stress. Lipid accumulation in bone marrow adipocytes and osteoblasts induces endoplasmic reticulum (ER) stress and mitochondrial dysfunction, both potent sources of ROS (78). Additionally, oxidized low-density lipoproteins (ox-LDL) accumulated in bone tissue can activate NOX enzymes, amplifying ROS production (79).

This bidirectional relationship creates a vicious cycle: GCs induce lipid accumulation → lipid deposition triggers oxidative stress → oxidative stress promotes lipid peroxidation → peroxides exacerbate oxidative damage and inflammation → further tissue injury. This lipid metabolism-oxidative stress axis represents an important therapeutic target, and interventions that simultaneously address both components may offer synergistic benefits in SINFH prevention and treatment.

3.7 The multidirectional crosstalk Among oxidative stress-mediated pathological processes

While the preceding sections have individually examined the effects of oxidative stress on osteogenic differentiation, osteoclast activation, apoptosis, vascular injury, and inflammation, these pathological processes do not operate in isolation. SINFH pathogenesis involves complex, bidirectional interactions among these mechanisms that create self-amplifying cycles of tissue damage.

Vascular Injury-ROS Amplification Loop: Vascular injury induced by oxidative stress leads to ischemia and hypoxia in femoral head tissue (80). Hypoxia, in turn, exacerbates oxidative stress through multiple mechanisms: (1) mitochondrial electron transport chain dysfunction during reoxygenation generates bursts of ROS; (2) hypoxia-inducible factor (HIF) activation can induce NOX expression; and (3) ischemic conditions deplete cellular antioxidant reserves (81, 82). This creates a vicious cycle where initial vascular damage amplifies oxidative stress, which further compromises vascular integrity.

Inflammation-ROS Vicious Cycle: ROS activates NF-κB, a master transcription factor for pro-inflammatory cytokines, leading to increased production of TNF-α, IL-1β, and IL-17 (83). These inflammatory mediators not only promote osteoclast activation but also stimulate further ROS production from macrophages and other immune cells (84). The resulting oxidative stress perpetuates inflammation, establishing a self-sustaining cycle that drives SINFH progression.

Apoptosis-Osteogenesis Imbalance: Oxidative stress-induced apoptosis of osteoblasts and BMSCs reduces the pool of cells available for bone formation and repair (30). Simultaneously, apoptotic cells release damage-associated molecular patterns (DAMPs) that activate inflammatory responses and promote osteoclast differentiation. This creates a situation where bone resorption exceeds formation, accelerating structural deterioration.

Lipid Metabolism-Oxidative Stress Interactions: Glucocorticoids promote adipogenic differentiation of BMSCs at the expense of osteogenesis, leading to lipid accumulation in bone marrow (85). Lipid deposition triggers oxidative stress through lipid peroxidation and mitochondrial dysfunction, while ROS further promotes adipogenesis and lipid oxidation, creating a metabolic vicious cycle. These interconnected pathological processes form a complex network where each mechanism influences and amplifies the others. This integrated perspective has important therapeutic implications: interventions targeting a single pathway may be insufficient, and optimal treatment strategies should aim to disrupt multiple nodes of this pathological network.

4 Oxidative stress-related signaling pathways in SINFH

Numerous signaling pathways are involved in the development of SINFH mediated by oxidative stress, especially the Nrf2/Keap1 signaling pathway, Wnt/β-catenin, and JNK/c-Jun signaling pathways. Therefore, these signaling pathways have important research value and may become therapeutic targets for SINFH. The following is a summary of the related signaling pathways to provide a reference for related research (Table 1).

Table 1. Signaling pathways associated with oxidative stress in ONFH.

zInterventionsIntervention objectsModel typeIntervention directionEvidence levelTherapeutic implicationRferences
Nrf2/ Keap1PARK7; platelet-rich plasmaBMSCsCell (rat BMSCs); Animal (rat)↓ ROS (PARK7, PRP)Moderate (in vivo with mechanistic insight)Potential to protect BMSCs from oxidative damageZhang (30), Wang (86)
Wnt/β-cateninSeNPs hydrogelBMSCsCell (rat BMSCs); Animal (rat)↓ ROS (SeNPs)Moderate (in vivo with mechanistic insight)Biomaterial-based approach for local antioxidant deliveryLiu (87)
AktAstragaloside IVHUCECs; BMSCsCell (human HUVECs, rat BMSCs); Animal (rat)↓ ROS (AS-IV)Moderate (in vivo with mechanistic insight)Multitarget herbal compound with osteogenic, angiogenic, and antioxidant effectsShan (88)
JNK/c-JunCrocin, N-acetylcysteine, proanthocyanidinsosteoblasts; PC12 cellsCell (rat osteoblasts, PC12)↓ ROS (all interventions)Preliminary (in vitro only)Potential to prevent glucocorticoid-induced osteoblast apoptosisChen (89) Peng (90)

4.1 Nrf2/Keap1 signaling pathway

The Nrf2/Keap1 signaling pathway is considered a classic pathway involved in oxidative stress. Nrf2 is a transcription factor that regulates intracellular oxidative stress and antioxidants. Free Nrf2 enters the cell nucleus and activates the gene expression of antioxidant enzymes such as MnSOD, CAT, and GPx, eliminating excess ROS, thereby protecting tissues from the effects of oxidative stress (30). PARK7 can promote the decomposition of the Nrf2/Keap1 complex, activate the gene expression of antioxidant enzymes such as CAT and GPx, thereby protecting BMSC from stress-induced apoptosis and inhibiting the development of SINFH (30). Wang et al. (86) found that platelet-rich plasma can activate the Keap1/Nrf2/HO-1 signal to reduce oxidative stress levels and promote the recovery of SINFH.

4.2 Wnt/β-catenin signaling pathway

The Wnt/β-catenin signaling pathway is crucial for cell proliferation and differentiation. In canonical pathway, Wnt binds cell surface receptors, Frizzled (Fz) and LDL-receptor related proteins (LRP5/6), and the signal is propagated through β-catenin signaling cascade (91). Research has found that oxidative stress can inhibit osteogenic differentiation through the Wnt/β-catenin and MAPK signaling pathways, accelerating the onset of SINFH. Liu et al. found that SeNPs can activate the Wnt/β-catenin signaling pathway under oxidative stress conditions and promote nerve regeneration (87).

4.3 Akt signaling pathway

Akt is the main downstream target of phosphoinositide 3-kinase (PI3K) that consists of catalytic (p110) and regulatory (p85) subunits. After the interaction of PI3K with the cell surface receptors, p110 is activated to produce the intracellular secondary messenger phosphatidylinositol-3,4,5-trisphosphate, which transfers Akt to the cell membrane and activates it. Additionally, Akt further activates the downstream target genes, glycogen synthase kinase-3β, mammalian target of rapamycin, nuclear factor kappa B, Bcl-xL/Bcl-2-associated death promoter (Bad), Nrf2 and hypoxia-inducible factor-1α (HIF-1α), regulating cell proliferation, differentiation and apoptosis (92). Akt acts on runt-related transcription factor 2 (Runx2) to regulate osteogenesis and on the hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway to regulate angiogenesis (93, 94); Nrf2/heme oxygenase-1 (HO-1) pathway to regulate oxidative stress (95); and Bcl-2 pathway to regulate apoptosis. Therefore, targeted regulation of Akt and its downstream related pathways to promote osteogenesis or angiogenesis and inhibit apoptosis or oxidative stress might offer effective means for the early prevention of SINFH. Among the several methods applied to prevent SINFH, monomers extracted from Chinese herbs have aroused widespread attention and may provide profound therapeutic benefits. Astragaloside IV (AS-IV) is an extract from Astragalus (Fisch), with various pharmacological effects, including promoting osteogenesis (96), anti-apoptosis (97), and antioxidant action (98). Shan (88) found that AS-IV inhibits cell apoptosis and oxidative stress through the Akt/Bad/Bcl-2 and Akt/Nrf2/HO-1 pathways, thus preventing SINFH induced by GCs. Phosphoinositide 3-kinases (PI3Ks) are part of the lipid kinase family and have the ability to phosphorylate inositol lipids within cells. This process regulates signal transduction and is involved in the transport of intracellular vesicles. Qin et al. discovered that the PIK3R5 gene, regulates the PI3K/AKT pathway through methylation modification, thus promoting cellular oxidative stress and expediting the progression of SINFH (99).

4.4 JNK/c-Jun signaling pathway

JNK is a key member of the MAPK family and plays a significant role in oxidative stress. ROS activates JNK, which induces the phosphorylation of c-Jun, accelerates the release and expression of caspase-3, and ultimately leads to cell apoptosis (89). Research conducted by Peng et al. (90) found that Dex induced an increase in the expression levels of Bax, Cleaved caspase-3, p-JNK, and p-c-Jun in osteoblasts, while the expression level of Bcl-2 decreased. This suggests that Dex's promotion of Bax expression is related to the activation of the JNK/c-Jun pathway. This implies that the activation of the JNK/c-Jun signaling pathway may be involved in Dex-induced osteoblast apoptosis. Crocin and NAC can significantly reduce the expression levels of Bax, Cleaved caspase-3, p-JNK, and p-c-Jun, while increasing the expression level of Bcl-2. By inhibiting the JNK/c-Jun signaling pathway, they suppress ROS-mediated cell apoptosis.

These signaling pathways are organized hierarchically in response to oxidative stress. ROS functions as an upstream activator that can simultaneously trigger multiple pathways through different mechanisms: direct oxidation of signaling proteins, activation of redox-sensitive transcription factors, and induction of cellular stress responses. The pathways then converge on common downstream effectors that regulate cell survival, differentiation, and apoptosis. Complex cross-talk exists among these signaling pathways, creating an integrated regulatory network. For example, Akt can phosphorylate Nrf2 at Ser40, promoting its nuclear translocation and enhancing antioxidant gene expression (100). Conversely, Nrf2 activation can modulate PI3K/Akt signaling through regulation of redox status. The Wnt/β-catenin pathway interacts with Nrf2 through β-catenin-mediated transcriptional regulation of antioxidant genes, while Nrf2 can influence β-catenin stability by regulating redox-sensitive proteasomal degradation (101). Additionally, JNK signaling can both activate and be modulated by these pathways—JNK-mediated phosphorylation of β-catenin can enhance its transcriptional activity, while Akt can suppress JNK activation through inhibition of upstream kinases.

Based on current evidence, these pathways can be comparatively evaluated for their importance in SINFH pathogenesis and therapeutic potential. The Nrf2/Keap1 pathway emerges as most promising for intervention due to: (1) its central role as the master regulator of the antioxidant response, controlling expression of multiple phase II detoxifying enzymes; (2) the availability of pharmacological activators (e.g., sulforaphane, dimethyl fumarate) with established safety profiles; and (3) its integration with other pathways, allowing modulation of broader cellular responses.

The Akt pathway ranks second in therapeutic potential given its unique position integrating multiple cellular functions—it simultaneously regulates osteogenesis (via Runx2), angiogenesis (via HIF-1α/VEGF), apoptosis (via Bad/Bcl-2), and oxidative stress (via Nrf2/HO-1). This pleiotropic effect makes Akt an attractive target, though the challenge lies in achieving pathway-specific modulation without affecting its diverse physiological functions. The Wnt/β-catenin pathway, while crucial for osteogenesis, shows less direct involvement in oxidative stress regulation compared to Nrf2. Its therapeutic potential may be best realized in combination strategies that simultaneously target oxidative stress and promote bone formation. The JNK/c-Jun pathway, though clearly involved in oxidative stress-induced apoptosis, presents challenges for therapeutic targeting due to its context-dependent effects and the risk of interfering with physiological JNK functions in other tissues.

5 Future perspectives

While substantial progress has been made in understanding the role of oxidative stress in SINFH, several critical research gaps and translation challenges must be addressed to translate these findings into clinical benefit. The clinical translation of antioxidant therapy for SINFH faces multiple bottlenecks despite promising preclinical results. Many potent antioxidants such as resveratrol and curcumin exhibit poor oral bioavailability and undergo rapid metabolism, limiting their therapeutic efficacy (102). Furthermore, achieving therapeutic concentrations specifically within the femoral head remains challenging due to the site's limited vascular access, though local delivery systems including hydrogels, 3D-printed scaffolds, and nanoparticles offer potential solutions that require optimization for clinical use (87, 103). The optimal timing of antioxidant intervention—whether before, during, or after glucocorticoid administration—also remains undefined; pre-treatment might prevent initial oxidative damage but could interfere with glucocorticoid's therapeutic effects, while post-treatment might be too late after irreversible damage has occurred. Additionally, the appropriate dosage, duration of therapy, and the influence of patient heterogeneity in genetic background, comorbidities, and disease stage on treatment response require systematic investigation.

Current clinical markers of oxidative stress, including MDA, SOD, and GSH, have significant limitations including poor specificity influenced by diet and circadian rhythm, lack of tissue specificity as serum levels may not reflect femoral head redox status, diurnal variation making single measurements unreliable, and lack of standardization across laboratories. Emerging biomarkers such as oxidized LDL, F2-isoprostanes, protein carbonyls, and 8-hydroxy-2′-deoxyguanosine offer improved specificity but require validation in SINFH cohorts, while imaging-based approaches such as redox-sensitive MRI contrast agents could potentially enable non-invasive assessment of femoral head redox status.

Given the multifactorial nature of SINFH pathogenesis, antioxidant monotherapy may be insufficient, and rational combination strategies targeting multiple pathological nodes simultaneously warrant investigation. These include combining antioxidants with angiogenic factors to address both oxidative damage and vascular insufficiency, with anti-inflammatory agents to break the inflammation-ROS cycle, with bone anabolic drugs to promote bone formation while protecting against oxidative damage, and utilizing lipid-lowering agents with antioxidant properties to target the lipid metabolism-oxidative stress axis.

Key scientific questions requiring investigation include the temporal sequence of oxidative stress relative to other pathological processes in SINFH development, the existence of critical windows for antioxidant intervention, whether genetic polymorphisms in antioxidant enzymes influence SINFH susceptibility, the potential of oxidative stress markers to predict SINFH progression or treatment response, and how different glucocorticoid regimens affect oxidative stress magnitude. Addressing these questions through well-designed preclinical and clinical studies will be essential for advancing oxidative stress-based therapies from bench to bedside.

6 Conclusions

In this research, we analyzed the role of oxidative stress in the diagnosis and treatment of SINFH from multiple perspectives, including bone metabolism, cell apoptosis, inflammatory response, and oxidative stress-related signaling pathways. The findings indicate that oxidative stress not only leads to cell damage and apoptosis but also exacerbates SINFH pathological progression by modulating bone metabolism, promoting inflammation, and altering related signaling pathway activity. Therefore, the regulation of oxidative stress provides new research directions for the prevention and alleviation of SINFH.

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Footnotes

Edited by: Milind B. Ratnaparkhe, ICAR-National Soybean Research Institute, India

Reviewed by: Junming Huang, The First Affiliated Hospital of Nanchang University, China

Wenbo Yang, Huazhong University of Science and Technology, China

Statements

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

The author(s) declared that financial support was not received for this work and/or its publication.

Author contributions

YW: Conceptualization, Writing – original draft. RM: Writing – review & editing. HJ: Supervision, Writing – review & editing, Conceptualization.

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Citation

Wu, Y., et al. (2026). Oxidative stress in steroid-induced necrosis of femoral head: a review revealing new insights into pathogenic mechanisms. Frontiers in Musculoskeletal Disorders, Volume 4. https://doi.org/
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4 - 2026

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© 2026 Wu, Ma and Jiang.

License: https://creativecommons.org/licenses/by/4.0/

*Correspondence: Hongjiang Jiang

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