Iron is one of the essential trace elements in the human body and is crucial for maintaining various biological functions, such as transporting oxygen, participating in the production of energy in the respiratory chain, and being involved in key biological reactions as a key component of various enzymes (34). However, iron accumulation can also mediate a series of pathophysiological processes, such as reactive oxygen species (ROS) production, lipid peroxide production and mitochondrial dysfunction, thereby promoting disease progression, such as SLE (35). Iron accumulation has been detected in the kidneys of both SLE patients and lupus mice (36, 37), and multiple molecules related to iron metabolism [such as ferritin, transferrin, ceruloplasmin, and neutrophil gelatinase-associated lipid carrier protein (NGAL)] have been identified as biomarkers of SLE and/or LN, which are associated with disease activity and/or renal involvement (38–43). Additionally, the excessive intake of iron exacerbates SLE progression (44–46), whereas iron chelation can alleviate the disease (37, 47).

Kidney is major damaged organ in SLE and main organ attacked by iron overload because it is site of iron filtration and reabsorption. Over transferrin bound (TBI) and non-transferrin bound iron (NTBI) can overwhelm the heavy chain ferritin (FtH) capacity, which lead to release of labile iron and render proximal tubular epithelial cells (PTEC) susceptible to iron oxidant damage, especial in distal tubular epithelial cells (DTEC) with lack iron storage (light and heavy chain ferritin) and export protein (ferroportin) (15). Moreover, this damage can be worse under some pathological condition like LN with glomerular injury resulting in an increased leakage of TBI and NTBI (48). Additionally, SLE is a typical autoimmune disease, and the overactivation of CD4⁺ T lymphocytes is a feature of SLE (28). In SLE, CD4⁺ T cells are over differentiated into pathogenic Th1 and Th17 cells, whereas Treg cells are suppressed (49, 50). Interestingly, iron is crucial for regulating the activation, proliferation and differentiation of CD4⁺ T lymphocytes (51). Some reports have demonstrated that the iron concentration in CD4⁺ T cells is significantly greater in SLE patients than in healthy controls (52, 53). CD71 (also referred to as ferritin receptor TfR1, which mediates iron endocytosis) on the surface of CD4⁺ T cells is essential for their activation and proliferation and promotes their differentiation into Th17 cells (54–56). Moreover, Th17 cells in SLE patients express high levels of CD71, which is positively correlated with disease activity (56). Similarly, follicular helper T (Tfh) cells, as a specific subset of CD4⁺ T cells, contribute to the pathogenesis of SLE by promoting the maturation of germinal center B cells and the production of antibodies (57, 58). However, the accumulation of iron in CD4⁺ T cells in SLE can promote their differentiation into Tfh cells and aggravate the progression of SLE (53). Moreover, Treg cells can restrict CD4⁺ T cell overactivation and its dysfunction is involved in SLE pathogenesis (59–61). Gao XF et al. demonstrated iron deficiency could alleviate pristane-induced lupus progression by promoting Treg cell expansion (62). And Feng P et al. verified iron overload leaded to systemic autoimmune disorders by aggravating Treg cell death (63). These findings verify that iron overload is involved in the pathogenesis of SLE, but whether it occurs through ferroptosis is not clear.

Iron overload is also conducive to ferroptosis. Too much iron intake, too little iron excretion, or impaired iron metabolism can contribute to iron overload. Physiologically, there are several ways to reduce the level of intracellular iron when the level of intracellular iron is excessive: i. iron-responsive proteins/iron-responsive elements (IRPs/IREs) hamper the transfer of iron by disrupting the stability of transferrin receptor mRNA while promoting the transcription and synthesis of ferritin to enhance the binding of free iron (64–66); ii. increased expression of hepcidin promotes the expression of iron transfer protein (ferroportin), which promotes iron outward transport (67–69); and iii. ferritin is targeted to lysosomes by nuclear receptor coactivator 4 (NCOA4)-mediated autophagosomes for degradation (often referred to as ferritinophagy) (70, 71). Iron overload is a vital trigger for ferroptosis. i.Iron-mediated Fenton reactions are necessary for ferroptosis and can facilitate the production of phospholipid hydroperoxides (PLOOH, a biomarker of ferroptosis). ii.Key enzymes that trigger lipid peroxidation [lipoxygenases (LOXs) and cytochrome P450 oxidoreductases (PORs)] require iron catalysis. iii.Iron is required for numerous redox-based metabolic processes and is a major source of intracellular ROS (11, 34). iv.Iron chelating agents not only prevent ferroptosis but also reduce the production of lipid peroxides (72–75). Feng P et al. reported that iron overload in Treg cells can promote iron-dependent cell death (63). Liu Y et al. shown iron overload in the joint cavity of rheumatoid arthritis patients and in vitro can promote ferroptosis in macrophages (76). Additionally, Alli, A. A. et al. demonstrated iron sequestration within the proximal tubules promoted LN progression by exacerbating ferroptosis (77). This evidence demonstrated that iron accumulation can trigger ferroptosis not only in the extracellular space but also in the intracellular space.

Thus, iron overload is a shared feature of SLE and ferroptosis and multiple evidences showed iron overload was involved in disease progression by triggering ferroptosis (Figure 1). Although, numerous reports demonstrated iron overload can aggravate the progression of SLE, whether the effect is ascribed to promoting ferroptosis. Anyhow, preventing iron accumulation in tissues and cells by mediating the key molecules of iron metabolism (transferrin receptor, ferroportin, hepcidin, etc.) may be a novel direction for the treatment of SLE.

Mitochondria are essential organelles for maintaining the normal physiological function of the cell and play a crucial role in physiological processes such as energy production, calcium homeostasis, and iron metabolism. It is also a key site for ROS elevation, self-nucleic acid antigen production, and the promotion of various forms of cell death (such as ferroptosis), which are closely related to a variety of diseases, such as SLE (26, 78, 79). Overactivation and immune intolerance of immune cells is the most pivotal link in the pathogenesis of SLE (28). The rapid proliferation and differentiation of immune cells require mitochondria to supply a large amount of energy. Oxidative phosphorylation (OXPHOS) of the electron transport chain (ETC) on the inner mitochondrial membrane is the process of ATP production, which is also accompanied by ROS production (80). Dysfunction of mitochondria limits ATP production but aggravates the release of ROS, which are closely related to immune disorders, autoantibody production, excessive cell death and ineffective clearance mechanisms (81). Previous studies have shown that mitochondria in CD4⁺ T cells from SLE patients exhibit numerous abnormalities, such as large size (mitochondrial fusion), membrane hyperpolarization (elevated mitochondrial transmembrane potential), ATP depletion, fragility, increased mitochondrial ROS (mtROS) and decreased antioxidant (GSH) levels (82–84). Moreover, massive ROS production in SLE patients is the main contributor to mitochondrial dysfunction (85). Second, mitochondrial DNA (mtDNA) oxidized by ROS (ox-mtDNA) has been identified as an important DAMP. Under normal physiological conditions, it can be dissociated from mitochondrial transcription factor A (TFAM) and degraded in lysosomes. However, in SLE, the restriction of TFAM function promotes the continuous accumulation of Ox-mtDNA. In addition, mtDNA that is released into the cytoplasm can not only activate cyclic GMP-AMP synthase (cGAS) or Toll-like receptors 9 (TLR9) to promote the production of IFNs (86, 87) but also serve as an antigen to directly activate the immune system to exacerbate autoantibody production (81). Since the kidney is one of the most involved organs in lupus and iron consumption is prevalent in it, mitochondrial are particularly susceptible to oxidative attack in glomerular and tubular cells. Tian Y at al. Demonstrated the molecular mechanism of iron-induced injury in these cells was contributed to mtROS overproduction (88). Remarkably, recent evidence demonstrated impairment of mitochondrial degradation in glomerular and tubular cells was implicated in proteinuria and renal failure in LN (16, 89, 90). Moreover, both mtROS and impair mitochondrial degradation promote Ox-mtDNA accumulation (91). On the other side, Ox-mtDNA can exacerbate mtROS production in a vicious cycle, which further aggravate the disease progression.

Moreover, mitochondria serve as central hubs for multiple forms of cell death, such as apoptosis, necroptosis, and pyroptosis, and are also key organelles that trigger ferroptosis (5, 78, 92). It is still debated whether mitochondria are necessary for ferroptosis. For example, some cells become insensitive to ferroptosis-inducing agents after the removal of mitochondria, whereas others do not (93, 94). Moreover, it has also been shown that mitochondria are required for erastin-induced ferroptosis but not for RSL3-induced ferroptosis (17). However, deficiency of optic atrophy protein 1 (OPA1), which maintains mitochondrial homeostasis and function, leads to resistance to both erastin- and RSL3-induced ferroptosis (95). In ferroptosis, significant changes in mitochondrial function and morphology are observed, including a decrease in volume, increase in membrane density, and decrease in ridge and ATP production (7). The role of mitochondria in triggering ferroptosis is explained as follows: First, mitochondria are one of the main sources of ROS and the key site of energy production and iron metabolism (65, 96). Mitochondrial dysfunction not only reduces ATP production but also contributes ETC to leaking large amounts of ROS (such as O₂·- and H₂O₂) and disturb iron homeostasis. H₂O₂ combines with the Fe²⁺-mediated Fenton cascade and further exacerbates the massive release of ROS, which promotes lipid peroxidation (97). Depletion of mtROS can alleviate mitochondrial ferroptosis (98). Second, the tricarboxylic acid cycle (TCA) cycle is located in the mitochondria. The mitochondrial TCA cycle can increase ferroptosis sensitivity (17). Glutamate metabolism is an important complementary part of the TCA cycle. In mitochondria, glutamine can be converted to glutamate and TCA intermediate metabolites (α-ketoglutarate, αKG), both of which can promote ferroptosis (99–101). Moreover, the inactive αKG dehydrogenase complex can prevent ferroptosis induced by cystine depletion (102). Additionally, ferroptosis has been identified as a form of autophagy-dependent cell death (103). And interesting, some reports demonstrated mtDNA could trigger autophagy-dependent ferroptosis by activating STING (33) and peroxisome proliferator activated receptor alpha (PPARα) (104). Moreover, mtDNA is prone to transform B- to Z-DNA structures under mtROS stress (105), which could promote ferroptosis by activating Z-DNA binding protein 1 (ZBP1) (106). These results suggest that mitochondrial dysfunction can promote ferroptosis.

In summary, in SLE patients, mtROS accumulation and mtDNA release may promote ferroptosis and subsequent release of intracellular antigens and DAMPs, thereby mediating the progression of SLE (Figure 2). Therefore, limiting mtROS production and mtDNA release to maintain mitochondrial function may be a promising treatment strategy for SLE.

Lipid metabolism is a major physiological process that includes catabolism [fatty acid oxidation (FAO)], anabolism (de novo lipogenesis) and storage [lipid droplets (LDs)], and lipid metabolism disorders are closely related to multiple pathological processes and diseases, including immune dysfunction and SLE (107). Dyslipidemia, a major type of lipid metabolic disruption, is most common in SLE patients (68%-100%) and is characterized primarily by increased plasma levels of very low-density lipoprotein (VLDL), triglyceride (TG) and total cholesterol (TC) but decreased high-density lipoprotein (HDL) levels (108). This disorder not only is closely related to SLE activity and organ involvement (including the cardiovascular system and kidney) but is also related to high mortality (109, 110). Among them, low HDL-cholesterol (HDL-c) levels are the most common sign of dyslipidemia in SLE patients (18, 111, 112). Under normal conditions, HDL performs anti-inflammatory and antioxidative functions despite its cholesterol efflux capacity. However, in SLE, it functions in an opposite manner with an uncertain mechanism (113, 114). Interestingly, a previous study demonstrated that limiting cholesterol flux could aggravate the IFN and ISG response in a STING-dependent manner in macrophages (115), and its precursor concentration, 7-dehydrocholesterol (7-DHC), could also significantly increase I-IFN production via the phosphatidylinositol 3-kinase (PI3K)-protein kinase B 3 (AKT3)-interferon regulatory factor 3 (IRF3) pathway (116). However, 7-DHC, as a precursor to form Vitamin D3 in the skin by solar ultraviolet B radiation, is the main source of Vitamin D. The deficiency Vitamin D is prevailed in SLE population and its supplementation seems to ameliorated the diseases (117), which may attribute that adequate level of Vitamin D prevents the synthesis of 7-DHC. Additionally, the metabolite of cholesterol, 7α, 25-dihydroxycholesterol (7α, 25-OHC), is dramatically elevated in the plasma of SLE patients and binds to the G protein-coupled receptor (GPCR) Epstein–Barr virus-induced gene 2 (EBI2) in macrophages to alleviate the IFN and ISG response for protecting against SLE progress (118). Consequently, homeostasis lipidemia, especially cholesterol metabolism, is crucial for SLE pathogenesis.

Additionally, lipids are highly vulnerable to oxidation, and many lipid peroxides, including oxidized HDL (ox-HDL), ox-LDL, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), have been identified as potential biomarkers for SLE and are related to disease activity (111, 118–121). Because oxidative stress is involved in the pathogenesis of SLE, aberrant oxylipins have been revealed in SLE patients by lipidomic analysis (122, 123). Oxylipin is a series of oxidative metabolites produced by polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), linoleic acid (LA), and alpha-linolenic acid (ALA), that undergo non-enzymatic or specific enzymatic [lipoxygenase (LOX) and cytochrome P450 (CYP450)] oxidations. Multiple oxylipins, such as 12-hydroxy-heptecotrienoic acid (12-HHTrE) and prostaglandin E1 (PGE1), are critical for SLE pathogenesis and have been identified as biomarkers for SLE pathogenesis (124, 125). Interestingly, the concentration of serum PUFAs is significantly decreased in SLE patients, which demonstrates that the antioxidant system is impaired and that lipid peroxidation is prevalent (107, 124). Moreover, lysophospholipids containing PUFA chains and lipid peroxidation substances (i.e., 4-hydroxyalkenals) strongly accumulate in the peripheral blood mononuclear cells of SLE patients (126). In summary, lipid metabolic disorder is one of the outstanding features in SLE, especially pertaining to oxidized-lipid metabolism.

Moreover, lipid metabolic disorder is essential for ferroptosis, because the executor of this cell death is lipid peroxidation, which triggers ion flux disturbances and ultimately plasma membrane permeabilization and fragmentation (127–129). Lipid metabolism is crucial for the initiation, propagation and termination of lipid peroxidation (130). PUFAs [especially AA (C20:4) and LA (C18:2)] are regarded as primary inducers of ferroptosis because whose bis-allylic hydrogens have relatively low bond dissociation energies and are more sensitive to lipid peroxidation (19, 131). In brief, the contributions of PUFAs to ferroptosis can be divided into two main categories: extension into the membrane and peroxidation. First, PUFAs are taken into the cell or converted by other lipids inside the cell. Then, extension can occur into membrane phospholipids (PUFA-PLs) via acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), which are very vulnerable to peroxidation. Second, PUFA-PLs are oxidated by lipoxygenases or via nonenzymatic autoxidation reactions [such as the Fenton reaction). The lipid peroxidation chain reaction is subsequently maintained by lipid radicals (such as the phospholipid peroxyl radical (PLOO·)] derived from lipid peroxidation. When antioxidative agents, including GPX4 and coenzyme Q10 (CoQ10), are depleted, the cell ultimately undergoes ferroptosis (132).

Although the direct relationship between SLE and ferroptosis related to lipid metabolism has not been reported, there are numerous potential connections as follows: i.The dyslipidemia feature of SLE further promotes cholesterol metabolic dysfunction, which can affect ferroptosis. The intermediate, isopentenyl pyrophosphate (IPP), is required for the synthesis of GPX4 (133, 134) and CoQ10 (135–137), which are known to prevent ferroptosis. Similarly, squalene (138, 139) and 7-DHC (140, 141) effectively prevent lipids from autoxidation and subsequent fragmentation (142). Furthermore, some enzymes related to cholesterol metabolism serve as potential suppressors of ferroptosis, such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in mitochondria (143) and sterol C5-desaturase (SCD5), whereas 7-dehydrocholesterol reductase (DHCR7) (140) and squalene monooxygenase (SQLE) (138) function as pro-ferroptostic molecules (3). Elevation of the cellular cholesterol content specifically restrains elevated lipid peroxidation and reduces susceptibility to ferroptosis by decreasing membrane fluidity (138). ii.PUFA, an inducer of ferroptosis, is significantly decreased in the extracellular space but increased in the intracellular space in SLE patients (Figure 3). Moreover, the levels of lipid peroxidation substances, especially MDA and 4-HNE (ferroptostic biomarkers), are markedly increased in SLE patients. Moreover, elevated MDA was related with multiple lupus manifestations (such as vasculitis, musculoskeletal, cutaneous and nephritis) (144–146). And also, the serum levels of anti-MDA IgG antibody positively were related with disease activity, active nephritis, inflammatory indictors and the consumption of complement factors (147). This phenomenon may be explained by the fact that PUFAs are taken into cells to be involved in ferroptosis in SLE patients.

Intracellular iron accumulation is the chief culprit of ferroptosis and can promote SLE progression, the therapeutical reagents to reduce iron concentration may be beneficial to treat SLE. Iron chelators, including deferiprone (DFP), dexrazoxane (DXZ) and deferoxamine (DFO), are commonly used in clinical. Although only few reports demonstrated DFO could alleviated SLE progression, multiple evidences confirmed those chelators performed an effectivity on some chronical diseases by preventing ferroptosis, such as osteoarthritis (184), I/R-induced injury (185), non-alcoholic steatohepatitis (204), neurodegeneration (205) and so on. Additionally, hepcidin, the iron-regulatory hormone, has been verified it could reduce progression and severity of LN by decreasing renal iron accumulation (47).

Mitochondrial dysfunction not only drivers ferroptostic process but promotes SLE progression. Recovering mitochondrial dysfunction to prevent ferroptosis may improve prognosis of SLE disease. Recent evidences demonstrated mTOR inhibition suppress ferroptosis by mediating mitochondrial dysfunction (186). Sirolimus is an mTOR inhibitor that server as an antifungal or immunosuppressive agent in clinical, which also effectively alleviates lupus mice manifestation (187, 188). Moreover, Lai ZW et al. demonstrated sirolimus improve SLE patient activity by recovering mitochondrial dysfunction (189). Metformin, commonly used in clinical to treat type II diabetes, can reduces oxidants by normalizing mitochondrial dysfunction (190, 191). Remarkably, it has been verified to improve SLE patients by recovering mitochondrial dysfunction (206–208). Additionally, MitoQ, as an analogue of CoQ10, special for preventing mtROS production, was shown to alleviate lupus mice (86, 192).

Lipid peroxidation is essential to ferroptosis and prevent the process was shown to improve numerous ferroptosis-related diseases. Thiazolidinediones (TZDs), including rosiglitazone, pioglitazone and troglitazone, are applied to treat type II diabetes. Remarkably, TZDs performed an ability to suppress ferroptosis though selectively inhibiting ACSL4 and reduce mortality in kidney-specific Gpx4 knockout mice (193, 194). Liproxstain-1 (Lip-1), a spiroquinoxalinamine derivative, was identified as a special ferroptostic inhibitor by high-throughput screening. Recent evidence shown it could alleviate MRL/lpr lupus mice symptom (172). Additionally, some lipid antioxidants also display potential therapeutical prospect as follow: i. CoQ10 is a major substrate of FSP1 that known as ferroptostic suppressor. The dietary supplement of it as a potential candidate for the treatment of various noncommunicable diseases (195). Moreover, its analogues, idebenone with better bioavailability and efficacy, was shown to attenuate murine lupus (196). ii. Vitamin K, resembled CoQ10 structure, was used to overcome warfarin poisoning in clinical practice and its supplementation could positively affect multiple chronical diseases (197). Interesting, it also was identified as a lipid radical-trapping antioxidant to prevent ferroptosis via FSP1-mediated pathway (198, 199).

As described above, the xCT and GSH-GPX4 pathway are identified as primary defense mechanism to ferroptosis. N-acetylcysteine (NAC), a precursor to cysteine, has been shown to prevent ferroptosis by increasing cysteine levels and facilitating the synthesis of γ-glutamyl-cysteine and GSH (200). And its supplement is potentially beneficial for comorbid disorders associated with heavy alcohol consumption (201) and Parkinson’s disease symptoms (202). Micronutrient selenium (Se) is essential for maintaining GPX4 activity. Optimal Se supplement could improve hemorrhagic and ischemic stroke prognosis via inhibiting ferroptosis in mice (79). Additionally, glycyrrhizin, extracted from the glycyrrhiza and commonly used in clinical, could alleviate acute liver failure by increasing GSH and GPX4, decreasing MDA, Fe²⁺, ROS to inhibit ferroptosis (203).