CD74 was the first non-polymorphic protein shown to associate with polymorphic major histocompatibility complex (MHC) class II molecules (50). Structurally, it comprises an N-terminal cytosolic tail, a transmembrane domain and a luminal C-terminal domain. The CD74 gene, located on chromosome 5, encodes four isoforms (50). CD74 is primarily expressed by professional antigen-presenting cells such as dendritic cells, B cells and macrophages, but it is also found in endothelial, epithelial and some mesenchymal cells (21).

Within the endoplasmic reticulum, CD74 assembles into trimers and functions as a chaperone for MHC class II molecules, which is why it is also known as the 'class II invariant chain' (50). CD74 is produced in excess to ensure availability for MIF binding, independent of MHC II expression. Leng et al (15) reported that CD74, synthesized using a coupled transcription-translation reticulocyte lysate system, binds to MIF in vitro. Notably, a 40-amino acid segment within the extracellular domain of CD74 (residues 109-149) was identified as essential for mediating this interaction. Each CD74 trimer is capable of binding three MIF molecules. D-DT, a homolog of MIF, also binds CD74, albeit with faster association and dissociation kinetics than MIF (34).

Some parasites, including Plasmodium, Entamoeba, Toxoplasma and Leishmania, express MIF homologs that may exploit the MIF-CD74 interaction to evade host immune responses (50). MIF binds to the CD74-CD44 receptor complex, mediating inflammatory cell recruitment through downstream CXCR2 and CXCR4 signaling. This MIF-receptor interaction also activates the anti-apoptotic gene Bcl-xL, enhancing B cell survival; however, the precise mechanisms remain under investigation (20,21).

Additionally, MIF, through its interaction with the CD74 receptor, plays a pivotal role in the regulation of various physiological processes. MIF facilitates cell survival by activating Syk tyrosine kinase and the PI3K/Akt signaling pathway, culminating in the intramembrane cleavage of CD74 and the release of its intracellular domain (CD74-ICD) (51-53). In macrophages, phosphorylation of CD74-ICD by protein kinase A, followed by CD44 recruitment, leads to the activation of Src-family kinases and downstream ERK1/2 signaling, thereby modulating cellular metabolism (54). MIF also influences cell adhesion via the intracellular MIF-binding protein, Jun activation domain-binding protein 1 (JAB1), which sustains MIF-induced ERK phosphorylation (55). Under hypoxic conditions, MIF enhances hypoxia-inducible factor 1α (HIF1α) expression through a CD74-dependent autocrine positive-feedback mechanism (56). Furthermore, MIF/CD74/CD44 signaling exerts an inhibitory effect on osteoclastogenesis by inducing Lyn phosphorylation, which attenuates the receptor activator of NF-κB ligand-mediated Gab2/c-Jun N-terminal kinase (JNK)-1/c-Jun and Syk/phospholipase Cγ signaling pathways, ultimately suppressing the activation of nuclear factor of activated T cells 1 (57). These mechanisms are listed in Table III.

CD74 plays an important role in tissue repair associated with inflammation, particularly in conditions such as inflammatory bowel disease, where it protects epithelial cells from oxidative stress in experimental models (50). MIF binding to CD74 activates the ERK1/2 pathway, a member of the mitogen-activated protein kinase (MAPK) family, which regulates cell proliferation, differentiation and stress responses (55,58). This interaction also enhances arachidonic acid metabolism, prostaglandin synthesis and Toll-like receptor expression via Ets-family transcription factors (59). Table IV illustrates additional downstream pathways activated by MIF-CD74 binding include PI3K/Akt, NF-κB and AMP-activated protein kinase (AMPK), all of which contribute to cellular survival, proliferation and metabolic regulation (28,50,58,60-65).

CD74 expression is upregulated by interferon-γ (IFN-γ), a key mediator of both innate and adaptive immunity (50). CD74 also exists in a soluble form, generated through proteolytic shedding of its ectodomain, which reduces the availability of the membrane-bound receptor for ligand interaction (50). Interactions between MIF and CD74 are further modulated by proteins such as ribosomal protein S19 and JAB1, both of which act as competitive inhibitors of MIF binding (50).

CD44 is a key co-receptor in MIF signaling and plays important roles in cellular adhesion, migration, lymphocyte activation and angiogenesis. CD44 primarily functions through extracellular matrix (ECM) adhesion mechanisms (21,66). The CD44 gene, located on chromosome 11p13, contains 19 exons in humans, while mice possess an additional variant exon (v1). CD44 is broadly expressed in lymphocytes, fibroblasts and smooth muscle cells.

CD44 has been studied in cancer due to the involvement of its splice variants in tumor progression (67). The extracellular domain of CD44 can bind to MIF, thereby modulating downstream signaling cascades, as illustrated in Fig. 2 (67). The splice variants v3 and v6 of CD44 are particularly elevated in T cells from patients with SLE and in fibroblast-like synoviocytes from patients with RA, contributing to enhanced invasiveness and inflammation (22). For MIF signal transduction to occur, CD74 and CD44 must form a cis-complex on the plasma membrane (68). This complex triggers the activation of Src-family tyrosine kinases and subsequent signaling through the PI3K/Akt and AMPK pathways (21). Binding of D-DT to the CD74/CD44 complex can also activate the ERK1/2 pathway (67). Beyond inflammation and cancer, CD44 has been implicated in metabolic diseases such as insulin resistance, likely due to its interactions with hyaluronan and modulation of MIF-related signaling (67).

CXCRs: CXCR2, CXCR4 and CXCR7. MIF directly binds to three CXCRs, CXCR2, CXCR4 and CXCR7, each with distinct expression profiles. CXCR2 is predominantly expressed on neutrophils and endothelial cells, while CXCR4 and CXCR7 have broader distributions, including hematopoietic, endothelial and neuronal cells (22). Although MIF shares low sequence homology with natural ligands, such as CXC motif chemokine ligand (CXCL8) and SDF-1 (CXCL12), it contains specific motifs that enable receptor binding upon protein folding. Notably, D-DT does not bind CXCR2 (34). The prototypical function of MIF, inhibition of macrophage migration, is mediated by CD74-dependent recruitment of inflammatory cells through CXCR2 and CXCR4 (22,32,33,43,50). MIF also promotes monocyte adhesion and transendothelial migration, involving chemokines such as CXCL1 and CXCL8 (33).

MIF recruits myeloid-derived suppressor cells (MDSCs) via CXCL2-CXCR2 signaling, activating the MAPK and NF-κB pathways (31). However, MIF does not always mimic natural chemokine signaling. For example, it fails to activate ERK1/2 in platelets that lack CD74, indicating that CD74 is essential for CXCR2/4-mediated MIF signaling (21). Neutralization of CD74 abrogates signal transduction, reinforcing its critical role (21). When MIF binds to CD74 in complex with CXCR2 or CXCR4, it activates ERK1/2 and Akt through Gαi-coupled signaling. This complex may undergo internalization, potentially exposing these receptors on the surface of various tumors suggests that MIF-mediated effects are highly context-dependent (68).

CXCR7 differs functionally from CXCR2 and CXCR4. Instead of initiating transient G-protein-coupled signaling, it shifts ERK1/2 activation toward a sustained β-arrestin-2-mediated pathway. Although CXCR7 was initially considered an atypical chemokine receptor, it is now recognized as a direct non-canonical receptor for MIF. MIF binding to CXCR7 can occur independently or in complex with CD74 and/or CXCR4, potentially modulating β-arrestin signaling and influencing cell migration and survival (20,21). CXCR7 has also been implicated in B cell trafficking and shown to activate ZAP-70, suggesting broader roles in immune regulation. These findings indicate that MIF may exert context-dependent effects through its interaction with CXCR7, distinct from classical chemokine pathways (21,22).

The TME refers to the cellular and molecular milieu surrounding a tumor within the host's biological system. The TME is composed of vascular structures, immune and inflammatory cells (often bone marrow-derived), fibroblasts, ECM and the dynamic interactions among these components within the lymphatic and circulatory systems (94,95). The TME contributes significantly to tumor heterogeneity, progression and drug resistance. Non-malignant cells within the TME often play pro-tumorigenic roles throughout carcinogenesis, supporting uncontrolled cellular proliferation (95). For tumor development and metastasis to occur, cancer cells must acquire the ability to migrate, degrade the ECM, survive in circulation and colonize distant tissues. According to Mantovani et al (96), tumor-associated macrophages (TAMs) are the most abundant immune cells in the TME, supporting tumor progression by facilitating intravasation and protecting tumor cells from immune attack (94,96).

The TME is typically hypoxic, promoting the expression of MIF and other pro-inflammatory cytokines (96) (Fig. 3). Chronic inflammation, particularly mediated by MIF, promotes angiogenesis, resistance to apoptosis and tumor growth, which are hallmarks of malignancy (97-101). MIF contributes directly to these processes by activating key oncogenic pathways such as NF-κB, which acts as both a tumor initiator and promoter, and by inducing COX-2, which facilitates chemotherapy resistance. MIF also enhances STAT3 signaling, impairing dendritic cell function and allowing tumor immune evasion. Additionally, hypoxia and aberrant vasculature reinforce acidosis within the TME, which, in conjunction with MIF activity, drives malignant transformation and sustains the activation of HIF1α (Fig. 3) (96,102).

RAS family mutations are among the most frequent in human cancer (96). The RAS/RAF/MEK/ERK pathway triggers the production of pro-tumor cytokines and chemokines (96). The interaction between NF-κB and H1F1α leads to the upregulation of TNF-α and CXCR4, the latter being crucial for metastasis and a positive feedback loop for MIF expression (Fig. 3) (103). MIF, when secreted by cancer-associated fibroblasts (CAFs), promotes tumor cell activation by suppressing IFN signaling and inhibiting p53-dependent apoptosis (94); it also increases IL-6 production and amplifies tumor-promoting signals via the CXCR4/MIF/IL-6 loop (103). MIF also contributes to the polarization of macrophages toward a pro-inflammatory M1-like profile, yet its ultimate effect depends on the NF-κB mediated balance between proand antitumor functions (104). Thus, targeting MIF, its receptors (such as CD74 and CXCR4) and downstream mediators is necessary to disrupt the self-amplifying oncogenic loop (105). In parallel, strategies that re-educate tumor-promoting macrophages by modulating NF-κB could enhance antitumor immunity (Fig. 3) (94,106).

Quantifying MIF may have prognostic utility. A 2019 study identified elevated MIF and IL-17A levels as risk factors for breast cancer (BC) in the Mexican population (107). Novel therapies such as HSP90 inhibitors suppress MIF production in colorectal cancer (CRC) epithelial cells (108). Targeting MIF has shown promise in reducing the proliferation, angiogenesis and aggressiveness of cancer including triple-negative BC (TNBC), genitourinary cancer and pancreatic cancer (103,104,109,110). Additionally, combining autophagy inhibition with MIF targeting has been proposed for improved outcomes in TNBC (109).

Similar to its role in BC, MIF significantly contributes to the progression of lung cancer, which remains the leading cause of cancer-related death in men and the second leading cause in women globally (112). Lung cancer is broadly classified into two main histological types: Non-small cell lung cancer (NSCLC) and small cell lung cancer (112). NSCLC represents 80-85% of all lung cancer cases, with over half of patients diagnosed at the advanced stages (112,113). MIF has a diagnostic and prognostic role by distinguishing normal lung tissues from NSCLC samples as well as correlating with elevated VEGF levels and increased microvessel density in tumors (114,115). Functionally, MIF promotes proliferation and inhibits apoptosis in NSCLC cell lines such as H460 and A549 (113).

At the molecular level, MIF is negatively regulated by microRNA-146a, a microRNA whose upregulation leads to reduced proliferation and increased apoptosis in lung cancer cells (115). Additionally, the CXCR4-upregulated MIF/IL-6 axis has been identified as a key driver of tumor-fibroblast crosstalk and NSCLC progression, suggesting therapeutic potential for CXCR4 inhibitors and MIF antagonists (103,113). MIF has also been associated with chemoresistance. Specifically, in cisplatin-resistant A549 and H460 cells, MIF expression is correlated with enhanced stemness and activation of the Src/CD155/MIF pathway, as well as upregulation of Notch1 and β-catenin. Inhibition of Src signaling has been shown to reduce these markers, supporting the strategy of combining Src inhibitors with chemotherapy in resistant NSCLC cases (116).

MIF also plays a key role in lung cancer metastasis, particularly to the brain, which occurs in up to 60% of NSCLC cases (117). Transcriptomic analysis by Liu et al (118) revealed high MIF expression in brain metastases. Additionally, blocking the MIF/CD74 axis enhances radiotherapy efficacy by shifting microglia toward the M1 antitumor phenotype, emphasizing the therapeutic value of targeting MIF in advanced NSCLC (117). In terms of therapeutic interventions, SCD-19, a small-molecule inhibitor that targets the tautomerase site of MIF, has demonstrated antitumor efficacy in a Lewis lung carcinoma model (119). Similarly, MD13, a PROTAC-based compound developed in China, induces MIF degradation and suppresses the MAPK pathway, inhibiting lung cancer cell growth (118).

In CRC, MIF contributes to inflammation-driven tumorigenesis and metastasis. The role of MIF in CRC parallels that observed in breast and lung cancer, reinforcing its broad relevance in oncology (120). One of the main mechanisms in the pathophysiology of this cancer involves the upregulation of CXCR4, a known MIF receptor, which enhances metastatic potential (121). Notably, CXCR4 is expressed in multiple cancer types, including breast, prostate and ovarian cancer, as well as immune cells such as B and T lymphocytes (121). Through interaction with CXCL12 and MIF, CXCR4 activates a variety of signaling cascades, including G protein, ERK, JNK and JAK/STAT pathways, that support tumor growth and spread (121,122). The CXCR4/MIF axis has thus emerged as a significant driver of CRC metastasis and a promising therapeutic target (121,122).

Elevated MIF expression has been detected in patients with CRC and is correlated with advanced disease stages (123). Moreover, the MIF gene-173G/C polymorphism has been associated with increased MIF protein expression and higher CRC susceptibility. Within the colonic microenvironment, elevated MIF may also influence intestinal cell kinetics and amplify inflammatory responses, creating conditions conductive to malignant transformation (120). These findings collectively highlight the importance of further research into MIF as both a biomarker and a therapeutic target in CRC.

High-expression MIF alleles have been identified as a risk factor for the development of SLE (35,131-133). Recent studies have focused on the role of MIF in glomerulonephritis, especially lupus nephritis (LN) (35,131-133). The relationship between MIF and active LN appears to be complex and may involve interactions with other molecules such as adiponectin or resistin. The presence of MIF in urine may reflect not only renal excretion but also local production by tubular epithelial cells or infiltrating leukocytes (133,134). MIF is considered a contributor to both disease activity and the cumulative damage associated with SLE.

Zhou et al (35) demonstrated that CD74, the receptor for MIF, is upregulated in kidney epithelial cells and antigen-presenting cells, and that this upregulation can be induced by IL-6 or IFN-γ in vitro, highlighting its potential role in the autoimmune processes of SLE. SLE progression often requires increasing steroid treatment, which appears to be correlated with type I IFN activity. IFN can induce MIF expression in a time- and dose-dependent manner (132,135). Beltrán-Ramírez et al (135) proposed that MIF may increase the expression of P-glycoprotein by upregulating inflammatory cytokines such as TNF-α and IL-6. A broader cytokine panel, incorporating temporal expression, has been suggested for defining additional SLE subsets (136).

While ISO-1, the prototypical MIF inhibitor, is not considered a viable therapeutic option due to its low potency, alternative strategies have been explored for SLE (137). Artesunate (ART), an antimalarial drug, has been shown to counteract the effects of type I IFNs by inhibiting STAT1 phosphorylation, resulting in stabilization or even regression of atherosclerotic plaques in experimental models. These findings point to the IFN/MIF axis as a novel target in SLE-associated atherosclerosis (132). Additionally, IMMU-115, a MIF-targeted therapy, has shown acceptable toxicity and preliminary efficacy in patients with SLE; it reduces LN symptoms, with disease suppression maintained for up to 24 weeks following the initial dose (138).

The role of MIF extends beyond SLE, playing a notable role in other autoimmune diseases such as PsA. PsA is a chronic inflammatory autoimmune disease marked by synovitis, enthesitis and aberrant bone remodeling, driven by dysregulated cytokine networks. Central to its pathogenesis is the IL-23/Th17 axis, with key cytokines such as IL-17, IL-22 and TNF-α playing pivotal roles in promoting inflammation, osteoclastogenesis and joint damage (139-143). Genetic predisposition, particularly involving HLA class I alleles such as HLA-B*27, and environmental triggers such as trauma and dysbiosis further contribute to the disease by amplifying aberrant immune responses (142,143).

MIF has emerged as a significant contributor to PsA pathogenesis. Secreted by macrophages, synovial fibroblasts and keratinocytes, MIF promotes synovial inflammation and joint destruction by enhancing the production of TNF-α, IL-17 and other cytokines, thereby sustaining the inflammatory loop and facilitating osteoclast (143,144). Compared with healthy controls, elevated serum and tissue levels of MIF have been documented in patients with PsA, supporting its involvement in disease pathology (140,145). Furthermore, genetic studies have implicated MIF promoter polymorphisms in the susceptibility to PsA. Notably, the-173 G>C variant, particularly the-173C allele and G/C genotype, has been associated with increased PsA risk in various populations, including Mexican Mestizos and British Caucasians (140,141,146) The CATT5/-173*C haplotype was also linked to psoriasis susceptibility in North Indian cohorts (145), reinforcing the relevance of MIF gene variants in psoriatic disease.

In psoriatic skin, MIF expression is upregulated in keratinocytes and endothelial cells, suggesting a broader role in the inflammatory processes of psoriatic disease beyond the joints (144). Experimental models further support this notion: MIF-deficient mice exhibit reduced keratinocyte hyperproliferation and inflammatory cell infiltration in psoriasiform dermatitis, indicating a potential mechanistic role for MIF in skin pathology (91). Despite these insights, additional studies are needed to fully delineate the multifaceted role of MIF in PsA and its potential as a biomarker or therapeutic target.

Like PsA and SLE, MS is another autoimmune disorder in which MIF plays a crucial role. MS is the most common non-traumatic disabling disease affecting young adults (147). While its underlying cause remains uncertain, it is described as a chronic, immune-mediated demyelinating disease of the central nervous system (CNS) (89). MS is commonly viewed as a two-stage phenomenon, with early inflammatory processes driving the relapsing-remitting form and later neurodegeneration contributing to a non-relapsing progressive phase (147). During neuroinflammation, macrophages and microglia are considered significant sources of MIF in the CNS. Increased MIF levels have been found in patients with progressive MS, which are correlated with disease severity and progression (147).

A 2019 study by Cavalli et al (148) suggested that upregulation of the MIF cytokine family signature may occur in CD4⁺ T cells in patients with clinically isolated syndrome, potentially contributing to MS pathogenesis and serving as an effective biomarker and therapeutic target. The expression of MIF, CXCR4 and CD74 appears to be tightly regulated via negative feedback mechanisms (149). Similarly, Guan et al (150) demonstrated using a murine model of experimental autoimmune encephalomyelitis (a model of human MS) that inhibiting the MIF-CD74 interaction suppresses microglial M1 polarization and induces an anti-inflammatory response. B cell arrest in early maturation stages (implicated in MS onset) has been partially associated with MIF downregulation, which correlates with decreased CD74 and increased CXCR4 expression (89,149,151,152). Upregulation of CXCR4 suppresses Fas, reducing the clearance of autoreactive immune cells and allowing naive B cells to escape immune tolerance (89,149,152).

The relationship between the MIF-173G>C polymorphism and MS remains under investigation. Current evidence suggest no association with disease susceptibility in the Turkish population (129). However, in the Mexican Mestizo male population, this polymorphism may act as a male-specific modifier, influencing disease severity and progression (153).

Novel therapeutic strategies targeting MIF continue to emerge for MS. For instance, Dra1 constructs strongly inhibit the activation and recruitment of brain-infiltrating T cells and CD11⁺CD45^high myeloid cells, which express elevated levels of CD74 following CNS damage. These constructs antagonize CD74 with high affinity, resulting in diminished MIF signaling. This treatment approach also shows potential in methamphetamine addiction and traumatic brain injury (154). Additionally, iguratimod (IGU), an anti-rheumatic drug, exhibits selective MIF inhibition both in vitro and in vivo, and demonstrates additive effects with glucocorticoids in autoimmune encephalitis models (155). Another promising drug is ibudilast, a MIF and phosphodiesterase inhibitor, which has shown efficacy in slowing brain atrophy in progressive MS (156). It is worth noting that MIF levels are not useful for distinguishing responders from non-responders to glucocorticoid treatment in patients with acute optic neuritis, as they reflect only ongoing inflammation seen in long-term MS progression (157).

As a more organ-specific autoimmune condition, AA exemplifies how the immunomodulatory role of MIF impacts localized immune privilege. AA is characterized by non-scaring hair loss, ranging from bald patches to total scalp involvement. The disease emerges when immune privilege is lost in hair follicles, and MIF has been implicated in this process due to its ability to suppress natural killer cell activity (92,158,159). Genetics, emotional stress and autoimmunity all play an important role in the pathogenesis of AA (158).

Based on these findings, Eldesouky et al (158), investigated the involvement of MIF in AA and vitiligo using a small cohort comprising 22 patients with AA, 20 patients with vitiligo and 20 healthy controls. The results showed that MIF levels were significantly elevated in both AA (8.477±4.1761 ng/ml) and vitiligo vulgaris (3.930±2.7071 ng/ml) compared with controls (0.725±0.5108 ng/ml) (P<0.01). Furthermore, MIF concentrations were positively correlated with disease severity in both conditions. The authors concluded that MIF may play a significant role in the pathogenesis of AA and vitiligo, and that targeting MIF could represent a promising therapeutic approach.

In 2020, Oh et al (160) investigated the application of conditioned medium (CM) from human umbilical cord blood-derived mesenchymal stem cells (MSCs) to improve hair growth and developed a method to reliably produce this optimized CM. Their results demonstrated that MIF was essential for the effects of the primed MSC-derived CM and identified it as a key modulator of the hair growth-related protein VEGF in dermal papilla cells. These findings strongly suggest that this method could counteract hair loss and serve as a promising agent for hair restoration.

Just as AA involves the immune targeting of hair follicles, vitiligo is another organ-specific autoimmune disease, marked by depigmentation due to CD8⁺ T cell-mediated melanocyte destruction. The average lesion is a totally amelanotic, non-textured and white macule, with progressive disfigurement (161-163). Emerging evidence suggests that vitiligo is associated with a weakened antioxidant system, leading to free radical-mediated melanocyte death or deregulated melanogenesis that may trigger autoimmunity (164). MIF concentrations vary throughout the disease stages, potentially acting as an inflammatory setpoint by regulating the release of proinflammatory molecules (161,162,164).

A Chinese study found that the MIF-173G/C polymorphism and increased serum MIF levels were associated with active non-segmental vitiligo (NSV), which accounts for 90% of vitiligo cases (165). In western Mexico, the-794 CATT 5-8 and -173 G>C MIF polymorphisms are similarly associated with increased NSV risk. Moreover, both serum and in situ MIF levels are correlated with active disease status (161). Research has proposed that MIF may play a fundamental role in skin development (161). Both soluble CD27 (sCD27) and MIF are considered reliable serum biomarkers for disease progression, although sCD27 may offer greater predictive value (162,166).

Vitiligo is currently treated with topical corticosteroids, immunomodulatory agents, vitamin D analogs, antioxidants, phototherapy, laser therapy and surgery. Narrowband UVB (311-313 nm) remains the standard treatment (162,163). Novel therapies targeting MIF-related pathways include JAK inhibitors, N-acetyl-p-benzoquinone imine, isoxazoline imine conjugates and amino acid-benzaldehyde analog conjugates (162,163). JAK inhibitors are currently in phase II trials for topical use in patients with vitiligo (163).

RA is a chronic, invasive autoimmune disease characterized by synovial inflammation, joint erosion and bone resorption. Although its etiology is not fully understood, macrophages are one of the most abundant cell types in the synovium. Their excessive activation, enhanced anti-apoptotic capacity and increased production of proinflammatory cytokines contribute to RA pathogenesis (167-170). MIF plays a central role in sustaining inflammation in RA by promoting the production of proinflammatory cytokines and tissue-degrading enzymes. MIF stimulates MIF synovial fibroblast proliferation, neutrophil chemotaxis and osteoclast differentiation (168). Notably, a Swedish study reported decreasing MIF levels in patients with RA, contrary to the commonly considered association between MIF and RA severity (171). A 2017 meta-analysis including Asian, Latin American and Caucasian populations showed significantly elevated circulating MIF levels in patients with RA and found associations between MIF-173C/G and -794CATT5-8 polymorphisms and disease susceptibility (167). In southern Mexico, these MIF polymorphisms were related to disease activity but not susceptibility, contrasting with findings from Western Mexico (172). Further research is needed to clarify these population-specific discrepancies, particularly in the cell-type-specific transcriptional regulation of MIF variants.

Additionally, MIF-173C/G and-794CATT5-8 polymorphisms also appear to influence Th17-associated cytokine secretion in peripheral blood mononuclear cells from patients with Cushing's syndrome and RA. Their differential expression suggests a regulatory role of MIF promoter haplotypes in inflammatory profiles (173). More recently, MIF has been implicated in the regulation of Th2 cytokines such as IL-25, IL-31 and IL-33, which may have immunomodulatory roles in RA (174).

The discovery of CD74 autoantibodies in the serum of patients with RA supports the role of CD74 as a T-cell antigen in spondyloarthritis, eliciting Th1 and Th17 responses (175). A study examining MIF receptor expression at different stages of RA emphasized the need for further investigation into sCD74 as a MIF decoy receptor, capable of down regulating receptor signaling. The same study identified CXCR7 as a scavenger receptor that stabilizes CXCR4 under inflammatory conditions by preventing its internalization and degradation (176). Since 2018, new treatment options have emerged, including Z-590, a MIF inhibitor, and isopsoralen (IPRN), both showing promise in controlling RA-associated inflammation (168,170).