Systemic lupus erythematosus (SLE), an autoimmune disease, is characterized by autoantibody production, persistent inflammation, and multiple tissue damage. This condition is induced by accumulation of cell remnants from various cell death pathways (1). Ferroptosis, a regulated necrosis process driven by iron-dependent lipid peroxidation, was first coined by Dixon et al. in 2012 (2, 3). Ferroptosis has been associated with various physiological and pathological processes, including autoimmunity [e.g., multiple sclerosis (4)], cutaneous diseases [e.g., melanoma (5, 6)] and skin wounds (7). Li et al. reported that neutrophil ferroptosis contributes to neutropenia and disease manifestations in SLE (8). The study by Li et al. is the first and only one to directly associate ferroptosis with lupus. Based on evidence from the existing limited number studies, we postulate that ferroptosis is a missing link in the vicious cycle of immune dysfunction, inflammation, and clinical manifestations in lupus. In this review, we elucidate on the significance of ferroptosis in lupus and how it may lead to inflammation and clinical manifestations.

Ferroptosis, a non-apoptotic form of cell death, is characterized by two major biochemical characteristics: iron accumulation and lipid peroxidation (9). Iron can directly generate reactive oxygen species (ROS) through the fenton reaction or increasing the activity of iron-dependent enzymes such as lipoxygenases (LOXs) or prolyl-hydroxylases, which are responsible for synthesis of lipid peroxidation, finally leading to ferroptosis (9). This process can be suppressed by deferoxamine (DFO), an iron chelator, implying that iron-dependent ROS is the major cause of ferroptotic cell death (2).

Interestingly, it has been documented that iron metabolism and lipid peroxidation play crucial roles in autoimmunity (10, 11). Iron deposition was observed within the kidneys of lupus nephritis (LN) mice models and during human auto-inflammatory diseases (12, 13). Multiple proteins with abilities to modulate iron homeostasis have been identified to be urinary SLE biomarkers (12). The proteins mentioned above include the iron carrier proteins neutrophil gelatinase-associated lipocalin (NGAL) (14), the iron storage protein ferritin and the iron transfer protein transferrin (15). Besides, the end products of lipid peroxidation cascades are generally recognized as lipid oxidative stress biomarkers, such as malondialdehyde (MDA), 4-hydroxynonenal (HNE), conjugated dienes (CD), and isoprostanes (16). These biomarkers were found to be significantly increased and positively correlated with disease activity in SLE (17, 18), strongly implicating the important role of lipid peroxidation in immunomodulation and autoimmunity. Unregulated oxidative stress in SLE leads to immune dysfunction, abnormal cell death signals, autoantibody production, and fatal comorbidities (19, 20).

Importantly, the successful treatment of ferroptosis inhibitors in lupus-prone mice models provided direct evidence for the role of ferroptosis in lupus pathogenesis. Hepcidin, a major iron modulator and the endogenous protective molecule against ferroptosis (21), has been shown to decrease free iron availability, reduce the renal infiltration of macrophages and T cells, and further ameliorate kidney inflammation, thereby attenuating the severity of LN in lupus-prone mice models (22). Another ferroptosis inhibitor, liproxstatin-1, was shown to efficiently suppress lipid ROS levels in neutrophils and significantly attenuate lupus in mice models (8).

The mechanisms and genetic networks regulating ferroptosis are complex, and are still being elucidated. The glutathione (GSH)-glutathione peroxidase 4 (GPX4) antioxidant axis is the core redox mechanism involved in ferroptosis inhibition. GSH acts as a necessary cofactor for the normal function of GPX4, an antioxidant enzyme that scavenges lipid peroxides (23). Inactivation of GPX4 by GSH depletion results in lipid peroxidation, ultimately leading to ferroptotic cell death. System x c − (SLC7A11 and SLC3A2) is the most upstream player in the GSH/GPX4 signaling cascade. Notably, suppressed intracellular GSH and GPX levels in lupus patients are correlated with disease severity (24, 25). Reversal of GSH depletion attenuated disease severity in lupus-prone mice models (26). GPX4, a selenoprotein family member, requires selenium, a micronutrient, for its biosynthesis (27). And selenium deficiency is a risk factor for inflammation and autoimmunity, conditions that are prevalent in autoimmune diseases patients (28). GSH-GPX activity could be upregulated in lupus patients after selenium supplementation (29).

Apart from the GSH-GPX4 axis, various signaling pathways with the ability to modulate ferroptosis have been identified and associated with immune modulation and autoimmunity ( Figure 1 ). AMP-activated protein kinase (AMPK), a sensor of cellular energy status, plays an energy stress-mediated protective role against ferroptosis (30), also as a key role in immune related diseases (31). AMPK activation exerts functions in metformin treatment of lupus by inhibiting B cell differentiation into germinal center and plasma cells (32). Another powerful antioxidant, coenzyme Q10 (CoQ10), which has shown beneficial effects in autoimmune diseases (33), can suppress lipid peroxidation and ferroptosis (34). The CoQ10 analog idebenone has been demonstrated that can attenuate murine lupus by modulating mitochondrial biology and reducing inflammation (35).

Most immune cell types are implicated in SLE pathogenesis, beyond the activation of B cells (36). The significance of ferroptosis in immune systems has been reported by various studies. During maturation, activation, and differentiation of immune cells, iron metabolism and lipid peroxidation are important signaling molecules (10, 37). These processes can be regulated by antioxidant molecules such as GSH and GPX4 (38). Therefore, we discussed the relationship between ferroptosis and immunity, with a focus on SLE-associated immune cells.

T cells in lupus patients have been correlated with abnormal mitochondrial hyperpolarization and adenosine triphosphate (ATP) depletion, which cause predisposition to death by necrosis (39). Swollen lymph nodes of lupus patients harbor increased numbers of necrotic T cells, leading to inflammation and tissue damage in SLE (39–41). GSH levels are lower in T cells from patients with SLE, and the reduction degrees of GSH are associated with mitochondrial hyperpolarization and increased reactive oxygen intermediates production (42). In particular, increased intracellular iron has been found in lupus CD4+ T cells compared with healthy controls (43). Based on these findings, the possibility of ferroptosis, one of the regulated necrosis, to contribute in lupus T cells can be proposed. Besides, both CD4⁺ and CD8⁺ T cells that lack GPX4 would rapidly accumulate membrane lipid ROS, and undergo ferroptosis, leading to their inability to expand and protect against viral and parasite infections (44).

B cells are the central elements of humoral immunity and protection due to their ability to produce antibodies. Aberrant activation and differentiation of B cells with pathogenic autoantibody production are recognized as pivotal roles in the immunopathogenesis of SLE (45). Compared to hepcidin-treated lupus mice models, as previously stated, the spleens of vehicle treated group contained anomalous dense iron deposits in B-cell regions (22). Iron plays an important role in B cell maturation, germinal center formation and immune responses (46). Higher ROS levels are essential for the process of B cell activation and differentiation (37). Lipid peroxidation induced by erastin, the classical ferroptosis activator, can promote the proliferation and differentiation of human peripheral blood mononuclear cells (PBMCs) into B cells and natural killer (NK) cells (47). These findings imply that ferroptosis may govern B cell differentiation and activity through lipid peroxidation. Nevertheless, the roles of ferroptosis in B cells remain unclear. Current research demonstrated that GPX4 is indispensable for innate-like B cells rather than follicular B2 cells to prevent ferroptosis (48). Given the importance and complexity of B cells in lupus development, there is a need to establish the significance of ferroptosis in B cells.

The function of macrophages is to eliminate pathogens and maintain immune homeostasis. Activated macrophages are traditionally classified into two main subsets: the pro-inflammatory subset (classically activated macrophages, M1) and the anti-inflammatory subset (alternatively activated macrophages, M2). Monocytes from SLE patients exhibit a remarkable pro-inflammatory (M1-like) profile, which is skewed towards the anti-inflammatory (M2-like) phenotype after recovery (49). Compared to M2 macrophages, M1 macrophages express higher levels of inducible nitric oxide synthase (iNOS), leading to higher resistance to ferroptosis (50). It may explain the imbalance in macrophage polarization during lupus progression: M1 phenotypes display significant defiance against ferroptosis, yet they can survive, release proinflammatory cytokines, and fulfill their functions as “destroyers”; while M2 phenotypes are vulnerable to ferroptotic cell death induced by the loss of GPX4 activity (51).

Neutrophils are the first responders of immune defense against a broad range of pathogens (52). Currently, the research about the link between neutrophils and lupus is mainly focused on neutrophil extracellular traps (NETs), the fibrous networks protruding from activated neutrophils in response to infection or inflammation (53). However, recent study by Li et al. demonstrated that neutrophil death is majorly associated with ferroptosis in SLE, instead of NETosis, the process of NET release. Through downregulated expression of GPX4 and elevated lipid ROS levels, neutrophil ferroptosis leads to stimulation of autoreactive B cells and plasmacytoid dendritic cells (pDCs), autoantibody and type I interferon (IFN) production, finally contributing to disease manifestations (8). Therefore, ferroptosis promotes lupus progression through immune system regulation.

Ferroptosis occurs in various immune cells and affects immune response as it has been described earlier. Further, ferroptosis regulates on how immune system deals with dying cells and remnants, through the release of damage-associated molecular patterns (DAMPs) or lipid oxidation products (9). DAMPs bind to cellular receptors such as pattern recognition receptors (PRRs), upregulate stress response mechanisms, and release various cytokines and chemokines, finally leading to tissue injury and inflammation (54). For example, the signals of high-mobility group box 1 (HMGB1), one of prototypical DAMPs released by ferroptotic cells, can be integrated by advanced glycosylation end-product specific receptor (AGER) to trigger inflammation and amplify immune responses (55). HMGB1 released by ferroptosis is implicated in multiple tissue damage, including ultraviolet B (UVB)-induced keratinocyte death (56), and high glucose-exposed mesangial cell death (57). Interestingly, HMGB1 activity plays a markable role in a variety of lupus phenotypes, including LN, neuropsychiatric lupus (58), and skin lesions (59). HMGB1 exerts its causative effects in SLE through both innate and adaptive immunity (58, 60), including macrophage polarization, pro-inflammatory cytokines secretion, and autoantibodies generation. Besides, iron accumulation can directly polarize macrophages to pro-inflammatory profile (61), promote pro-inflammatory cytokine secretion to induce autoimmune diseases (13); ROS facilitates inflammatory disease via pro-inflammatory change (62). Massive lipid oxidative mediators released by ferroptosis directly promote the activity of cyclooxygenases (COXs) and LOXs, which convert arachidonic acid to inflammatory mediators; this process can be suppressed by GPX4 (63). Therefore, it is speculated that ferroptosis may exert its pathogenic effect in SLE by excessive inflammation, which enhances immune response, leading to organ damage and clinical manifestations. A potential model is proposed for the role of ferroptosis in lupus inflammation and induced comorbidities ( Figure 2 ).

With respect to skin, keratinocyte death by ferroptosis plays a remarkable role in driving skin inflammation after UVB exposure (56). Skin lesions suffered from UVB irradiation shows elevated iron content (64), excessive accumulation of lipid peroxides, and GSH depletion, therefore undergoing ferroptosis in keratinocytes, and then leads to cutaneous necroinflammation and injury (56). Furthermore, UVB-induced skin damage can be protected by GSH and GPX4 through suppressing oxidant stress, inflammation responses, and cell death (65). Based on the lupus photosensitivity, and ROS accumulation in all cutaneous subtypes of lupus (66), the cutaneous lesions may be associated with dysregulation of iron metabolism and the consequent ferroptosis induced by UV irradiation.

LN is one of the most severe organ manifestations of lupus, which most patients would develop within 5 years of SLE diagnosis (67). Tubulointerstitial damage is recognized as one of the pathological features of the lupus kidney, and tubulointerstitial inflammation is important in the assessment and prognosis of LN (68, 69). Within this local microenvironment, renal tubular epithelial cells (RTEC) are central effector cells, driving interstitial inflammation and renal damage (70). As mentioned above, renal iron accumulation occurs in LN and contributes to the development of albuminuria (12). RTECs reabsorb the majority of filtered iron (71), and these cells have been shown to undergo ferroptosis under pathological conditions (72, 73). Treatment of lupus mice models with iron metabolism regulators, such as deferiprone and hepcidin, could mitigate kidney inflammation and delay lupus progression (12, 22). Besides, uncontrolled ROS accumulation in RTECs results in inflammation and fibrosis, leading to renal damage and chronic kidney disease progression (74). Thus, it could be speculated that iron accumulation in RTECs may exacerbate inflammatory responses by ROS formation, and synergistically accelerate progression to renal failure. Meanwhile, inflammation and oxidative stress can upregulate the expression of iron carriers and transporters, possibly causing excessive uptake of iron in the renal tubules and consequent iron-induced kidney injury (75).

For cardiovascular system, the oxidation of low-density lipoproteins (oxLDL) by ROS and the activation of endothelial cells in the artery, are recognized as initiation of atherosclerosis in SLE (76). Endothelial cells stimulated by oxLDL release inflammatory cytokines, induce chronic inflammation, finally leading to endothelial dysfunction and cardiovascular injury (76). In addition, lupus patients with progressive atherosclerosis exhibit decreased levels of high-density lipoprotein (HDL) and dysfunctional HDL (77). HDL is a natural antioxidant agent and act as a protective mechanism of atherosclerosis in SLE, protecting LDL from oxidation by ROS in the arterial intima (76, 78). Recently, a study by Bai et al. used ferroptosis inhibitor, ferrostatin-1, to treat high-fat diet-induced atherosclerosis (79). They found that Fer-1 could alleviate atherosclerosis lesion and rescue endothelial dysfunction, through inhibition of iron accumulation and lipid peroxidation, and upregulation the expression of SLC7A11 and GPX4. Compelling evidence links ferroptosis to the initiation and progression of atherosclerosis.

In conclusion, ferroptosis is speculated to be an integral component in the vicious cycle of immune dysfunction, inflammation, and tissue damage in lupus. This review article indicates that ferroptosis has outstanding research prospects in the progression of SLE. However, it is suggested that more future studies should be conducted to fill the knowledge gaps of the relationship between ferroptosis and SLE, shed more light on the pathogenesis of SLE, as well as provide a new perspective on ferroptosis-based immunotherapy for SLE.

Conceptualization: QC, JW, JL, and JX. Funding Acquisition: JW, JL, and JX. Methodology: QC, JW, JL, MX, YW, ZZ, and JX. Supervision: QC, JW, JL, MX, YW, ZZ, and JX. Writing – Original Draft Preparation: QC. Writing - Review and Editing: QC and JW. All authors assisted with the development of the manuscript and gave final approval for publication.

This work was supported by grants from the National Natural Science Foundation of China (grant no. 81773324, 81872526); and the Startup Foundation of Huashan Hospital (2020QD007).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.