Neuroinflammation and astrocyte dysfunction are associated with schizophrenia. To elucidate the molecular mechanisms involved, we generated induced pluripotent stem cells from 14 schizophrenia patients and 14 healthy controls and differentiated them to human cortical spheroids. Transcriptional profiling revealed overexpression of cilia-related genes in schizophrenia spheroids which was mainly driven by astrocytes. We identified baseline abnormal astrocyte distribution in schizophrenia and show that it is triggered by the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF), primarily secreted by neurons. While treatment with the MIF antagonist ISO-1 attenuated abnormal astrocyte distribution in schizophrenia spheroids and reduced pro-inflammatory cytokines secretion, MIF gene knockout with CRISPR-Cas9 exacerbated astrocyte and cytokines dysregulation in schizophrenia cultures, suggesting that both extremes of elevated and absent MIF lead to impaired astrocyte distribution and that a minimum expression of MIF is required for optimal cell function. Taken together, our results point to a MIF-induced regulation of cortical astroglia in schizophrenia and highlight MIF antagonists as potential novel treatment strategies.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive disease marked by excessive extracellular matrix deposition and deteriorating lung function. Although macrophage migration inhibitory factor (MIF) has been implicated in pulmonary fibrosis, the downstream mechanisms-particularly whether MIF drives fibrosis through its receptor CD74-remain insufficiently understood. This study investigated whether MIF/CD74 signaling promotes fibroblast activation through specific downstream pathways that regulate proliferation and matrix production. Single-cell RNA sequencing and ELISA were used to characterize MIF-CD74 interactions and circulating MIF levels in IPF patients. Bleomycin-induced fibrosis models were established using C57BL/6J mice, Mif⁻/⁻ mice, and the MIF inhibitor 4-IPP. Macrophage-fibroblast co-culture systems were treated with bleomycin, 4-IPP, or CD74 shRNA. Lung injury, fibrosis, and signaling activation were assessed by histology, qRT-PCR, Western blotting, and functional assays. scRNA-seq identified MIF-CD74 as a dominant macrophage-fibroblast signaling axis in fibrotic lungs, and serum MIF levels were elevated in IPF patients. In mice, bleomycin markedly increased MIF and CD74 expression and activated MAPK signaling. Genetic deletion or pharmacologic inhibition of MIF attenuated collagen deposition, improved lung architecture, and reduced profibrotic and inflammatory signaling. In vitro, MIF promoted fibroblast proliferation, migration, and matrix synthesis, whereas CD74 knockdown or MIF inhibition significantly attenuated fibroblast profibrotic responses. MIF promotes pulmonary fibrosis by activating CD74-dependent MAPK signaling in fibroblasts, enhancing their proliferation and extracellular matrix production. Targeting the MIF/CD74 axis reduces tissue remodeling and represents a promising therapeutic strategy for IPF.

Background Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder characterized by generalized loss of sweating without identifiable causes. Because few biomarkers reflect its underlying mechanisms, diagnosis at the initial visit is often difficult. Although steroid pulse therapy is widely used, approximately half of patients respond insufficiently. We therefore aimed to elucidate the immune mechanisms underlying AIGA and identify potential biomarkers for diagnosis and treatment response. Methods Fourteen patients with AIGA affecting more than 25% of body surface area were enrolled after exclusion of secondary causes of anhidrosis. Serum levels of 40 cytokines and chemokines were quantified using a multiplex assay and correlated with clinical parameters. Skin biopsy specimens were analyzed by histology and immunohistochemistry to characterize inflammatory cell infiltration and identify cellular sources of selected mediators. Results Inflammatory cell infiltration was consistently observed around sweat ducts, predominantly composed of CD4 + T cells. Serum profiling revealed significant elevations of CCL22 and IFN-γ in AIGA compared with healthy controls, with a strong positive correlation between them. Consistently, the downstream chemokine CXCL10 was also increased. Double immunostaining identified CD68 + macrophages as the main source of CCL22 in periductal regions. Serum Macrophage migration inhibitory factor (MIF) levels were significantly higher in steroid-resistant cases, whereas MIF expression within sweat ducts was markedly reduced, suggesting disruption of local immune privilege. Conclusions These findings suggest that AIGA involves a macrophage–CCL22–Th1–IFN-γ inflammatory axis associated with collapse of sweat duct immune privilege. Serum MIF may serve as a potential biomarker for predicting steroid responsiveness.

This study investigated the association between aerobic exercise preconditioning and macrophage migration inhibitory factor (MIF) expression, as well as myelination in sciatic nerve in experimental autoimmune neuritis (EAN) rats. Female Lewis rats underwent 4-week swimming protocols including High-intensity daily (HI-Daily), Moderate-intensity daily (MOD-Daily), and Moderate-intensity alternate-day (MOD-AltDay) regimens prior to EAN induction, with control groups of EAN without exercise and Sham operation. Assessment of disease severity, nerve conduction velocity, and sciatic nerve pathology revealed that the moderate-intensity alternate-day exercise regimen significantly delayed disease onset, lowered peak clinical scores, and improved neurological function. Molecular analyses demonstrated that this protective effect was mediated through divergent regulation of MIF: systemic MIF was substantially suppressed (27205.94 ± 4291.76 pg/mL vs EAN 71075.61 ± 10166.41 pg/mL; p<0.001) with concomitant reduction in macrophage infiltration, while local MIF expression within the sciatic nerve was significantly elevated (p<0.01), correlating with enhanced remyelination as evidenced by increased myelin sheath area (LFB: 67.42 ± 3.26% vs EAN 40.64 ± 9.63%, p<0.01) and elevated myelin basic protein expression (0.92 ± 0.14 AU vs EAN 0.59 ± 0.02 AU, p<0.05). Crucially, both high-intensity daily and moderate-intensity daily exercise protocols failed to confer comparable benefits. These findings indicate that the protective effect of MOD-AltDay exercise preconditioning on EAN is associated with tissue-specific regulation of MIF, and this change correlates with reduced systemic inflammation and enhanced local remyelination. Pharmacological/genetic studies are needed to confirm mechanisms and evaluate this exercise regimen as a non-pharmacological intervention for autoimmune neuropathy.

Macrophage migration inhibitory factor (MIF) promotes inflammation, regulates immune responses and chemotherapy resistance in the tumor microenvironment. However, its mechanism of action in colorectal cancer (CRC) metabolic reprogramming and targeted therapeutic potential remain unclear. This study aims to investigate the function, mechanism, and targeted therapeutic potential of MIF in CRC. Data were integrated from TCGA, GTEx, CPTAC, and HPA databases with clinical sample validation. Single-cell sequencing analysis (datasets GSE166555 and GSE144735) was performed, alongside functional assays and mechanistic studies. A novel high-potency MIF inhibitor was identified through virtual screening and validated in vitro and in vivo. MIF expression was found to be significantly elevated in CRC tissues and cell lines, correlating with poor overall survival (OS) and disease-specific survival (DSS). Single-cell sequencing confirmed malignant epithelial cells as the primary MIF source. Functional assays demonstrated that MIF knockout suppressed CRC cell proliferation, migration, and tumor growth in vivo, while MIF overexpression promoted these effects. Mechanistically, MIF binds CD74 to upregulate glycolytic enzymes (HK2, PKM2, LDHA), enhancing glucose uptake and lactate/pyruvate production, thereby driving the Warburg effect and CRC progression. Virtual screening identified a novel high-potency MIF inhibitor, F3277-0933 (IC50 = 8.284 μM). In vitro and in vivo, F3277-0933 surpassed the classical inhibitor ISO-1 in suppressing MIF-driven glycolytic reprogramming and proliferation. This study elucidates a novel mechanism by which the MIF-CD74 axis drives CRC progression through glycolytic reprogramming and provides robust preclinical evidence for developing MIF-targeted therapies.

UBTF-HSP90A-MIF stress circuit drives lenvatinib resistance and immune exclusion in hepatocellular carcinoma.

Purpose.Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine implicated in many inflammatory and fibrotic diseases; however, its role in primary open-angle glaucoma (POAG) and trabecular meshwork (TM) dysfunction remains unknown. In this study, we investigated whether MIF-CD74 signaling regulates TM pathobiology through modulation of the transcription factor, Blimp-1, and downstream cytoskeletal reorganization and extracellular matrix (ECM) remodeling.Method.Primary human TM cells (HTMC) were exposed to glaucomatous stressors, including TGF-β2, rMIF, or a pro-inflammatory milieu. Expression of MIF, its receptor CD74, and Blimp-1 was measured by qPCR and immunoblotting. ECM proteins and phosphorylated myosin-light chain (pMLC) were evaluated by immunofluorescence staining. In vivo, MIF-CD74 and Blimp-1 expression were examined in the TM/anterior segment (AS) tissue of Tg.CreMYOCY437H and lentiviral (LV)-TGF-β2-induced ocular hypertension (OHT) mouse models. Functional involvement of MIF signaling in TM pathobiology was examined using the irreversible MIF inhibitor 4-IPP and the immunomodulatory metabolites agmatine and thiamine.Results.Glaucomatous stressors significantly upregulated MIF and CD74 expression with concomitant suppression of Blimp-1 in HTMC. Similarly, TM/AS tissue from both OHT models (Tg.CreMYOCY437H and LV-TGF-β2) demonstrated increased MIF-CD74 expression accompanied by reduced Blimp-1 levels. Activation of MIF-CD74 signaling triggered pro-inflammatory and cell death pathways and promoted ECM remodeling, characterized by increased fibrotic protein expression and enhanced RhoA/ROCK-mediated MLC phosphorylation, indicating modulation of TM contractility. Pharmacological inhibition of MIF attenuated inflammatory signaling, reduced ECM deposition and cytoskeletal remodeling, and suppressed RhoA/ROCK/MLC activation, restoring a protective TM phenotype.Conclusion.Our findings identify MIF-CD74 signaling as a previously unrecognized regulator of TM dysfunction in POAG. MIF-mediated suppression of Blimp-1 mechanistically links inflammatory signaling to cytoskeletal contractility and fibrotic ECM remodeling, key determinants of aqueous humor outflow resistance. Targeting the MIF-CD74/Blimp-1 axis may represent a novel therapeutic strategy to restore TM homeostasis and reduce intraocular pressure in glaucoma.

Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for more deaths than any other malignancy. Despite advances in treatment, it remains highly lethal, with 5-year survival rates showing minimal improvement over the past several decades, highlighting a critical unmet clinical need. Macrophage Migration Inhibitory Factor (MIF) is a multifunctional cytokine that contributes to inflammation and cancer, promoting tumor growth, progression, and metastasis through modulation of the tumor microenvironment, stimulation of angiogenesis, and regulation of immune responses. Polymorphisms in the promoter region of MIF, such as high-expression CATT repeats, influence MIF expression and susceptibility to a range of inflammatory, autoimmune, and malignant disorders, yet their role in lung cancer remains largely unexplored. Therapeutic strategies targeting MIF, including small-molecule inhibitors, antibodies, and peptide-based agents, have shown promise in preclinical models, although their clinical translation is still limited. This review discusses the dual role of MIF in inflammation and oncology, summarizes current therapeutic developments, and emphasizes the potential of MIF-targeted interventions in lung cancer. It discusses the significance of genetic predisposition, particularly high-expression MIF alleles, in guiding personalized treatment strategies for lung cancer and identifying patients who may derive benefit from MIF inhibition.

Ultraviolet B (UVB) is a well-recognized trigger of cutaneous lupus erythematosus (CLE), yet its molecular basis remains largely undefined. Here, using single-cell transcriptomics and a lupus-prone mouse model, we identify keratinocyte-derived macrophage migration inhibitory factor (MIF) as a key amplifier of cutaneous inflammation through a self-sustaining feedback loop. Single-cell RNA sequencing reveals elevated MIF expression specifically within pathogenic, interferon-high keratinocyte subclusters associated with CLE, which is further validated across major CLE subtypes in clinical skin samples. In vitro, UVB irradiation dose-dependently induces the release of MIF from keratinocytes, which in turn promotes inflammatory signaling and matrix remodeling in both keratinocytes and fibroblasts. Mechanistically, we demonstrate that UVB irradiation activates the ribotoxic stress response (RSR), leading to the p38-C/EBPβ-mediated transcriptional upregulation of NLRP3 and GSDMD cleavage in keratinocytes. The ensuing GSDMD-dependent pyroptosis facilitates the release of MIF, primarily through GSDMD pores rather than vesicular secretion, which in turn amplifies the p38-C/EBPβ signaling pathway. Therapeutic disruption of this loop either by gene silencing via AAVs or pharmacological inhibition via microneedles, markedly attenuates epidermal hyperplasia and cytokine imbalance in lupus-prone mice. These findings uncover a previously unrecognized MIF-p38-GSDMD inflammatory loop contributes to the UVB-induced cutaneous lupus, offering both mechanistic insights and translational opportunities for CLE.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, particularly in the presence of liver metastases. The mechanisms by which metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), influences PDAC progression and metastasis remain poorly understood. This study investigates the role of MASLD in fostering an immunosuppressive microenvironment conducive to PDAC liver metastases and identifies the macrophage migration inhibitory factor (MIF)-CD44 axis as a key mediator of this process. Utilizing data from the UK Biobank (450,754 participants, median follow-up 14.5 years), we observed an overall increased risk of PDAC in the MASLD population (HR: 3.48; 95% CI: 2.69–4.50; P < 0.0001). Clinical cohorts confirmed the strong association between MASLD and hepatic metastases (OR: 7.06; 95% CI: 4.62–10.78; P < 0.0001). Experimental mouse models demonstrated that MASLD enhances tumor cell stemness, immune evasion, and focal adhesion in metastatic liver tissues. Mechanistically, MASLD-induced MIF secretion promotes CD44-positive PDAC cell migration, stemness, and adhesion. Targeting MIF, either genetically or pharmacologically using the MIF tautomerase inhibitor IPG1576 significantly attenuated liver metastasis in preclinical models. Validation in patient samples revealed elevated hepatic MIF and CD44 expression in MASLD-associated PDAC liver metastases. This study highlights the MIF-CD44 axis as a promising therapeutic target and underscores the importance of tailoring treatments for PDAC patients with concurrent MASLD.

Macrophage migration inhibitory factor (MIF) contributes to the progression of diverse malignancies. However, its expression and relation with systemic immune-inflammatory characteristics in predicting lymph node metastasis (LNM) in endometrial cancer (EC) remains unclear. The current study evaluates the association between MIF-related inflammatory features and LNM, and establishes a preoperative model for predicting LNM in EC. The current study enrolled 361 EC patients, and their clinical characteristics, hematologic parameters, tumor biomarkers, inflammatory indices, imaging features, and preoperative pathological findings were collected. MIF expression and relevant immune-inflammatory indicators were analyzed for their correlations with LNM. Independent predictors were identified using multivariable logistic regression. Model performance was assessed using ROC curves, calibration plots, and decision curve analysis (DCA). Among the 361 patients, LNM occurred in 51 patients (15.8%). Patients with LNM had significantly higher levels of CA125, HE4, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and larger tumor diameter. Myometrial invasion ≥1/2, cervical stromal involvement, and non-endometrioid histology were all significantly more frequent in the LNM group. Multivariate logistic regression identified high MIF expression, SII (per 100 units), myometrial invasion ≥50%, LVSI, and high-grade histology as independent predictors of LNM. The nomogram demonstrated excellent discriminatory performance, good calibration, and favorable clinical utility on decision curve analysis. Tumor MIF expression is an independent predictor of LNM in EC. Incorporation of MIF into a clinically grounded prediction model may enhance preoperative risk stratification of EC.

Fibroblasts are abundant structural cells with an emerging immune-sentinel role in the wound healing process, though its functional significance remains incompletely explored. By utilizing an oral injury model that heals rapidly, we identify murine PI16+ reticular fibroblasts to be enriched in interleukin-33 (IL-33), an alarmin cytokine, and demonstrate that Il33 deletion in fibroblasts impairs oral wound healing. Single-cell RNA sequencing analysis points to regulatory T (Treg) cells, which respond to IL-33 by upregulating the expression of macrophage migration-inhibitory factor (MIF) and transforming growth factor β1 (TGF-β1). Mechanistically, MIF promotes monocyte recruitment, which facilitates angiogenesis, whereas TGF-β1 is linked to early macrophage transition to a pro-resolving phenotype. Importantly, human oral mucosa harbors IL-33+PI16+ fibroblasts in the reticular layer of connective tissue, and Treg cells express MIF and TGFB1 in regenerating human oral mucosa. These results unveil a crucial role of IL-33-expressing oral fibroblasts for modulating inflammation in healing wounds via Treg cell activation.

To analyze the effect of metabolic disorders and immunological parameters on the functional outcome (FO) of acute ischemic stroke (IS) in patients with metabolic syndrome (MS). 298 patients in the acute period of IS were assessed. All patients were divided into two groups: Group 1 included 158 MS patients with a history of IS; Group 2 included 140 post-stroke patients without MS. The assessment included measurements of waist circumference, triglycerides (TG), low and high density lipoproteins (LDL/HDL), glucose, serum interleukins (IL-1b, IL-6, IL-16, IL-8), interferon gamma (IFN-g), tumor necrosis factor-alpha (TNF-α), macrophage migration inhibitory factor (MIF), monocyte chemotactic proteins (MCP-1/CCL2, MCP-3/CCL7), and macrophage inflammatory proteins (MIP-1a/CCL3, MIP-1d/CCL15). Patient disability rates measured by the modified Rankin Scale (mRS) at Day 21 from the IS onset were considered as FO parameters. The FO evaluation revealed a significant (p<0.0001) prevalence of patients with an unfavorable/relatively unfavorable outcome (mRS ≥3) in Group 1. In the cohort of MS patients, multivariate mathematical analysis (correlation analysis and machine learning methods) showed the relationship of FO with the levels of LDL (r=0.520, p.d.=0.055), glucose (r=0.850, p.d.=0.089), the number of metabolic factors (r=0.880, p.d.=0.111), the concentrations of CCL3 (r=0.840, p.d.=0.354), CCL2 (r=0.520, p.d.=0.281), and MIF (r=0.830, p.d.=0.156). A worse FO score was observed in patients with MS than in metabolically healthy patients, and this was associated with hypercholesterolemia, hyperglycemia, the number of metabolic factors, and the expression of CCL3, CCL2, and MIF.

CSB6B attenuates renal inflammation and fibrosis by inhibiting the activation of NLRP3 inflammasome through the NLRP3/Caspase-1/GSDMD/IL-1β signaling pathway.

Chronic kidney disease (CKD) is characterized by gradual and progressive deterioration of renal function over time, and its pathogenesis is strongly associated with immune cell imbalance, Th cell diversification, and oxidative stress. This study aimed to investigate the impact of alterations in the Th17/Treg ratio mediated by the secretory protein macrophage migration inhibitory factor (MIF) on renal injury in CKD patients. Single-cell sequencing was performed on peripheral blood mononuclear cell (PBMC) from 15 CKD patients and 20 healthy individuals to compare the characteristics of T-cell subsets, followed by differential signaling pathway analysis. Peripheral blood samples from 20 CKD patients and 10 healthy donors were analyzed using flow cytometry to quantify CD4 + T cell subsets and MIF expression. A 5/6 nephrectomy mouse model and blood CD4 + T cells were extracted to verify the effects of MIF-related proteins on the Th17/Treg ratio and progression of CKD. Besides, AAV-MIF was locally administered into the renal tissue to achieve kidney-specific MIF suppression in CKD model. Single-cell sequencing revealed significant correlation between MIF levels and Th17/Treg ratios, identifying MIF-(CD74 + CXCR4) pathway involvement. Flow cytometry analysis of the clinical cohort demonstrated an elevated Th17/Treg ratio (p < 0.01) in CKD patients compared to normal controls. MIF levels also correlated with renal parameters (Crea, p < 0.001; BUN, p < 0.0001; eGFR, p < 0.0001). In vitro experiments confirmed a significant increase (p < 0.05) in Th17/Treg cells after MIF protein or serum from CKD patients, and these changes were partially reversed by an MIF inhibitor (ISO-1) (p < 0.001). Moreover, renal injury in CKD mice in the AAV-MIF group was significantly reversed. This study revealed that MIF promotes the progression of CKD by regulating the Th17/Treg ratio and that MIF serves as a potential target to prevent CKD.Graphical MIF regulates the Th17/Treg ratio to exacerbate kidney injury in chronic kidney diseaseSupplementary InformationThe online version contains supplementary material available at 10.1007/s10753-025-02418-x.

The role of autophagy in glioma remains controversial, with long non-coding RNAs (lncRNAs) playing a crucial role in its regulation. N6-methyladenosine (m6A) modification influences lncRNA expression and function. Specifically, lncRNA EIF3J-AS1 acts as an oncogene in glioma, yet the mechanisms driving its upregulation remain unclear. This study demonstrates that EIF3J-AS1 expression is significantly elevated in glioblastoma multiforme (GBM) compared to low-grade glioma (LGG) and normal brain tissue. RNA sequencing (RNA-seq) identified EIF3J-AS1 as a target of the tumor suppressor miR-101, with functional assays showing its role in promoting glioma cell proliferation, inhibiting autophagy, and enhancing tumorigenesis in vivo. Methylated RNA immunoprecipitation (MeRIP) and bioinformatics analyses confirmed m6A modification of EIF3J-AS1, which correlates positively with the m6A methyltransferase METTL3 in glioma tissues. Mechanistically, METTL3 promotes m6A-dependent binding of EIF3J-AS1 to the transcription factor FOXG1. RNA-seq screening further identified macrophage migration inhibitory factor (MIF), an autophagy-promoting gene, as a downstream target of both METTL3 and EIF3J-AS1. Functional validation revealed that the METTL3/EIF3J-AS1/FOXG1 axis suppresses autophagy via MIF downregulation. Conversely, miR-101-mediated suppression of METTL3 disrupts EIF3J-AS1-FOXG1 binding, restoring MIF expression and promoting autophagy. These findings highlight EIF3J-AS1 and METTL3 as potential therapeutic targets, with disruption of EIF3J-AS1-FOXG1 interactions representing a novel autophagy-modulating strategy for glioma treatment.

Lung adenocarcinoma (LUAD), a predominant subtype of non-small cell lung cancer (NSCLC), is characterized by a complex tumor microenvironment (TME) that drives immune evasion and contributes to variable clinical outcomes. This study investigates the role of tumor-derived macrophage migration inhibitory factor (MIF) on immune modulation and prognosis in LUAD. Single-cell RNA sequencing (scRNA-seq) data from three LUAD tumors (E-MTAB-6149; 29,936 cells) were analyzed with Seurat to identify cell types and marker genes. Cell-cell communication was assessed using CellChat, and prognostic significance was evaluated in the TCGA-LUAD cohort with GEPIA2. Malignant cells showed the highest expression of MIF, which may interact with CD74 + CXCR4 + and CD74 + CD44 + receptor complexes on B cells, T cells, and myeloid cells, consistent with known MIF-mediated signaling pathways. A predominant B cell subset (59%) expressing CD74 or CXCR4 (termed as MIFR+ B cells) showed elevated expression of MHC class II genes (such as HLA-DRA and HLA-DPB1) and co-stimulatory genes (such as CD40 and CD83), indicating antigen-presenting cell (APC)-like functions. High MIF expression was associated with a poor prognosis in TRU-subtype LUAD [hazard ratio (HR)=2.5, p-value=0.029], while MIFR+ B cell signatures was correlated with improved survival. Tumor-derived MIF is associated with poor prognosis, likely by suppressing the immune system, but it also promotes the induction of APC-like B cells, which are associated with improved outcomes, highlighting its dual role in LUAD. These findings position MIF as a potential therapeutic target and suggest that MIFR+ B cells could serve as important prognostic markers.

BackgroundIntracranial aneurysms (IAs) develop and progress through pathological processes, including inflammation and abnormal changes in the vascular structure. The cytokine Macrophage Migration Inhibitory Factor (MIF) is implicated in the pathology of vascular diseases. However, the role of MIF in IAs remains to be elucidated.MethodsTranscriptomic data from IA and normal arteries were analyzed to quantify MIF expression and immune infiltration (CIBERSORT). Methylation sequencing assessed MIF promoter methylation. Single-cell RNA sequencing (scRNA-seq) defined secretory vascular smooth muscle cell (sVSMC) and M1-like macrophage proportions and MIF expression. Intercellular communication via the MIF-CD74 axis was evaluated using CellChat. In vitro functional experiments validated sVSMC-induced macrophage M1 polarization mechanisms.ResultsMIF mRNA was significantly upregulated in IAs (diagnostic AUC = 0.89) and correlated with increased M1-like macrophage infiltration (r = 0.783, p = 0.008). Hypomethylation of MIF was observed in IAs. scRNA-seq revealed expanded secretory VSMCs and M1-like macrophages, with elevated MIF in secretory VSMCs. CellChat confirmed enhanced MIF-CD74 signaling. In vitro, secretory VSMCs induced M1 polarization (iNOS/CD86↑, Arg1↓) via MIF-CD74; this effect was reversed by MIF knockdown or CD74 inhibition.ConclusionWe provide a comprehensive single-cell atlas of IAs and identify the sVSMC-derived MIF-CD74 axis as a novel mechanism driving macrophage M1 polarization and IA inflammation. This uncovers previously unrecognized sVSMC-macrophage crosstalk, establishing the MIF-CD74 axis as a promising immunomodulatory target for IA therapy.

Macrophage migration inhibitory factor (MIF) is one of several pivotal cytokines that contribute to orchestrate immune regulation, inflammation, and cell survival, acting as both a mediator of host defense and a factor that viruses can exploit. This comprehensive review delineates MIF's multifaceted roles across diverse viral families-including Retroviridae, Herpesviridae, Hepadnaviridae, Orthomyxoviridae, Flaviviridae, Paramyxoviridae, and Picornaviridae-highlighting the mechanisms by which viruses manipulate MIF signaling to promote replication, evade immune responses, and induce tissue damage. Viral strategies often involve upregulating MIF expression or leveraging its receptor pathways, such as CD74, CXCR2, and CXCR4, to enhance viral persistence, disrupt barrier integrity, and skew immune polarization toward pro-viral or immunosuppressive states. Conversely, MIF-driven inflammation can worsen pathogenic processes, including cytokine storms, neuroinvasion, and fibrosis, contributing to disease severity. Notably, pharmacologic inhibition of MIF has shown promise in preclinical models, reducing viral replication and mitigating tissue damage, thereby positioning MIF as one of the compelling targets for host-directed antiviral therapies. Understanding the complex, context-dependent functions of MIF in viral infections provides transformative insights for innovative treatment strategies that aim to disrupt virus-host interactions, control inflammation, and improve clinical outcomes in infectious diseases. Future research exploring MIF's molecular interactions, genetic variations, and therapeutic modulation will be crucial for harnessing its potential for personalized, effective antiviral interventions.

Identification of the MIF-CD74/CD44 signaling axis as a therapeutic target in pediatric Acute Myeloid Leukemia