Molecular Immunology[JOURNAL]
Sun
200 papers
Immunorestorative effects of caraway and marjoram extracts on Th2-mediated inflammation in house dust mite-triggered asthma.
Refaat AM, Mohammed HS, Ali F … +3 more , Mohamed H, Abdallah R, Abdel-Salam BKA
Mol Immunol · 2026 Jun · PMID 42013767 · Publisher ↗
Allergic airway inflammation, a hallmark of asthma, is commonly driven by environmental allergens such as house dust mite (HDM). This study examined the protective effects of caraway (Carum carvi) and marjoram (Origanum...
Allergic airway inflammation, a hallmark of asthma, is commonly driven by environmental allergens such as house dust mite (HDM). This study examined the protective effects of caraway (Carum carvi) and marjoram (Origanum majorana) extracts in a rat model of HDM-induced allergic airway inflammation. Daily HDM intranasal administration was applied over four weeks, with or without concurrent oral administration of the herbal extracts. Both treatments significantly reduced airway inflammation, total serum IgE, and pro-inflammatory cytokines (IL-6 and TNF-α), as well as the regulatory cytokine IL-10 in bronchoalveolar lavage fluid (BALF). RT-qPCR revealed a marked downregulation of Th2-associated cytokines (IL-4, IL-5, and IL-13) and the mucus-related gene Muc5ac, along with the restoration of the regulatory marker Foxp3. Consistently, ELISA analysis of BALF showed partial recovery of the Th1 cytokine IFN-γ. Western blotting confirmed reduced protein expression of NF-κB and STAT6 in treated groups. Histological examination showed notable improvement in lung architecture. Collectively, these findings suggest that caraway and marjoram attenuate HDM-induced airway inflammation through immunomodulatory and anti-inflammatory mechanisms, supporting their potential as complementary therapeutic agents for allergic asthma.
The role of macrophage metabolic reprogramming in efferocytosis: A dual-edged sword in atherosclerosis and tumor progression.
Chen Q, Liu C, Wang Q … +4 more , Zhang X, Zheng Y, Guo M, Wang J
Mol Immunol · 2026 Jun · PMID 42000693 · Publisher ↗
Macrophage efferocytosis-the process by which macrophages recognize, engulf, and degrade apoptotic cells (ACs)-is essential for maintaining tissue homeostasis and resolving inflammation. Dysregulation of efferocytosis ha...
Macrophage efferocytosis-the process by which macrophages recognize, engulf, and degrade apoptotic cells (ACs)-is essential for maintaining tissue homeostasis and resolving inflammation. Dysregulation of efferocytosis has been implicated in the progression of various diseases, including atherosclerosis (AS) and cancer. In AS, effective efferocytosis reduces inflammation, stabilizes plaques, and slows disease progression. Conversely, in the tumor microenvironment (TME), efferocytosis contributes to immune suppression, supporting cancer cell survival, proliferation, and metastasis. Impaired efferocytosis leads to the accumulation of secondary necrotic ACs, which exacerbate inflammation. Interestingly, in tumors, this process can paradoxically induce pro-inflammatory, anti-tumor immune responses. Therefore, understanding the regulatory mechanisms controlling efferocytosis is critical for the development of targeted therapies for inflammatory diseases and cancer. Recent findings highlight macrophage metabolic reprogramming as a key modulator of efferocytosis. Metabolic pathways, including glycolysis, amino acid metabolism, and fatty acid oxidation (FAO), provide the energy and biosynthetic intermediates necessary for macrophages to execute efferocytosis efficiently. These pathways influence all stages of efferocytosis-recognition, engulfment, and degradation of ACs-while shaping macrophage function and inflammatory responses. Moreover, metabolic adaptations in macrophages exhibit context-specific roles in atherosclerotic plaques and the TME, underscoring the complex and disease-specific effects of efferocytosis in pathological conditions. This review synthesizes current knowledge on the molecular mechanisms underlying efferocytosis and its regulation through macrophage metabolic reprogramming. It discusses how metabolic shifts impact efferocytosis and explores their broader implications in AS and cancer. Understanding the intricate interplay between macrophage metabolism and efferocytosis presents new opportunities for therapeutic intervention, with the potential to transform the clinical management of inflammatory and neoplastic diseases.
The role of apolipoprotein C1 in mediating pyroptosis in Hashimoto's thyroiditis via TLR10/MyD88/NF-κB pathway.
Sun B, Tan J, Yu S … +4 more , Ge J, Wei Z, Lei S, Li G
Mol Immunol · 2026 Jun · PMID 41996849 · Publisher ↗
BACKGROUND: Inflammation is an important pathogenic factor that leads to thyroid follicular epithelial cells injury after Hashimoto's thyroiditis (HT). Recent studies proposed relationships between pyroptosis and apolipo...
BACKGROUND: Inflammation is an important pathogenic factor that leads to thyroid follicular epithelial cells injury after Hashimoto's thyroiditis (HT). Recent studies proposed relationships between pyroptosis and apolipoproteins in HT. However, the molecular signatures involved in the pathophysiological changes that occur during the course of HT remain ambiguous. METHODS: The current study obtained thyroid tissues from HT patients and investigated the genes and pathways involved in HT by transcriptome sequencing analysis. Besides, ELISA, immunohistochemical staining, western blot analysis, LDH release assay and RNA interference were conducted to validate the expression levels of dysregulated proteins and underlying pathways. RESULTS: Transcriptomic analysis demonstrated that HT was associated with the enrichment of genes related to the inflammatory response, pyroptosis, and regulation of the lipid metabolic process. The transcription level of APOC1 gene ranked highest among apolipoproteins, and genes associated with the interleukin (IL)-18 signaling pathway and the NLRP3 inflammasome were upregulated. The expression levels of IL-18, NLRP3, and APOC1 proteins were increased in HT patients. Furthermore, in vitro studies using LPS-treated Nthy-ori 3-1 thyroid cells confirmed that APOC1 induced pyroptosis through TLR10/MyD88/NF-κB p65 dependent pathway. CONCLUSIONS: APOC1 probably participated in the pathogenesis of HT by mediating TFCs pyroptosis through TLR10/MyD88/NF-κB pathway.
Anti-inflammatory and barrier-protective effects of Lactiplantibacillus plantarum WB4303 and WB4304 via modulation of NF-κB and MAPK signaling in LPS-stimulated HT-29 cells.
Lee ES, Yun HJ, Min SJ … +3 more , Park JY, Lee NK, Paik HD
Mol Immunol · 2026 Jun · PMID 41990419 · Publisher ↗
Two newly isolated Lactiplantibacillus plantarum strains, WB4303 and WB4304, were obtained from Korean kimchi. Using an LPS-induced HT-29 intestinal epithelial cell model, we investigated their integrated functional prop...
Two newly isolated Lactiplantibacillus plantarum strains, WB4303 and WB4304, were obtained from Korean kimchi. Using an LPS-induced HT-29 intestinal epithelial cell model, we investigated their integrated functional properties. Both strains exhibited strong antimicrobial activity against intestinal pathogens and effectively inhibited pathogen adhesion via competitive exclusion. Gene and protein expression analyses revealed that L. plantarum WB4303 and L. plantarum WB4304 suppressed pro-inflammatory cytokines by modulating the nuclear factor-κB and mitogen-activated protein kinase signaling pathways. Notably, L. plantarum WB4303 restored tight junction-related gene expression and increased MUC2 and serotonin transporter levels, indicating additional barrier-enhancing and neuroimmune-modulatory potential. Collectively, these findings demonstrate the strain-specific functional diversity of kimchi-derived L. plantarum and support the potential application of L. plantarum WB4303 and L. plantarum WB4304 as targeted probiotic candidates for intestinal inflammatory conditions.
Molecular sensitization patterns to mammalian allergens - possible impact on diagnostics and therapy.
Khatri K, O'Malley A, Wright EM … +4 more , Kitlas P, Mias GI, Kowal K, Chruszcz M
Mol Immunol · 2026 Jun · PMID 41985225 · Full text
Growing ownership and presence of pets in households have contributed to increasing cases of pet-related allergies globally. In this study, we aim to analyze molecular sensitization patterns towards pet animals among a g...
Growing ownership and presence of pets in households have contributed to increasing cases of pet-related allergies globally. In this study, we aim to analyze molecular sensitization patterns towards pet animals among a group of individuals (n = 84) who were experiencing respiratory symptoms upon exposure to furry pets. Specific IgEs (sIgEs) towards furry animal allergens from 84 individuals were tested in vitro using the ALEX (Allergy Explorer) macroarray. The sequence and structural homology of common pet allergens were analyzed to evaluate the molecular basis of sensitization. Tested individuals showed allergic responses towards 20 allergens belonging to secretoglobin, lipocalin, and serum albumin protein families from cat, dog, horse, rabbit, mouse, guinea pig, hamster, and cow. Sensitization towards cats and dogs was found to be dominant, and cat allergen Fel d 1 was identified as the major sensitizer for the tested population, with 84.5% of patients having IgE against the protein. Major dog allergens were shown to be Can f 1 (32.1% of patients reacting) and Can f 6 (26.1%). The majority of the population (61.9%) had IgE to multiple allergens, largely within the lipocalin and serum albumin allergen families. This study reports higher sensitization towards cat and dog allergens for the individuals incorporated in the study. Understanding patterns of IgE sensitization to pets may help in diagnosis and development of better allergy treatments.
Salivary pathobiont Klebsiella pneumoniae exacerbating periodontitis-related intestinal dyshomeostasis and accelerated metabolic syndrome.
Lyu J, Wu M, Wei W … +7 more , Li J, Xiong K, Shen X, Gao X, Yang J, Li M, Tang B
Mol Immunol · 2026 Jun · PMID 41967182 · Publisher ↗
OBJECTIVE: The relationship between periodontitis and diabetes is well-established, yet the underlying mechanisms are incompletely understood. This study aimed to investigate the role of Klebsiella pneumoniae (Kp94), iso...
OBJECTIVE: The relationship between periodontitis and diabetes is well-established, yet the underlying mechanisms are incompletely understood. This study aimed to investigate the role of Klebsiella pneumoniae (Kp94), isolated from the salivary microbiota of periodontitis patients, in exacerbating diabetes by disrupting intestinal immunity and metabolic homeostasis. DESIGN: Following the induction of periodontitis by ligation and oral gavage of Kp94, the systemic metabolic status of the mice was assessed through the Disease Activity Index (DAI), intraperitoneal glucose tolerance test (IPGTT), and measurements of serum total cholesterol (TC) and glycated hemoglobin (HbA1c). To investigate the underlying mechanisms, transcriptomic analysis of intestinal tissues and 16S rRNA sequencing of intestinal contents were performed. Furthermore, intestinal immunity was evaluated by immunohistochemistry/immunofluorescence, and the proportion of ILC3s was analyzed by flow cytometry. RESULTS: Kp94 induced gut microbiota dysbiosis and systemic glucose intolerance. Mechanistically, Kp94 suppressed the intestinal ILC3/IL-22 pathway, which impaired mucosal immunity by reducing antimicrobial peptide (BD3, LCN2) expression, disrupting the mucus barrier, and increasing intestinal permeability. Concomitantly, this suppression inhibited endocrine function, notably GLP-1 production. Crucially, IL-22 administration rescued these defects by alleviating endoplasmic reticulum stress, thereby restoring barrier and endocrine integrity, and improving metabolic parameters, including HbA1c. CONCLUSION: Our findings suggest that the intestinal ILC3/IL-22 pathway may serve as a potential mechanistic link and therapeutic target for the metabolic and pancreatic damage associated with Kp94 in periodontitis-related diabetes.
PZP deficiency impairs M2 macrophage polarization via TGF-β/Smad3 signaling, contributing to immune dysregulation at the maternal-fetal interface in preeclampsia.
Yan M, Yang H, He W … +5 more , Lei H, Feng N, Guan W, Feng W, Han L
Mol Immunol · 2026 Jun · PMID 41967181 · Publisher ↗
BACKGROUND: Preeclampsia (PE) is characterized by immune dysregulation at the maternal-fetal interface, particularly an imbalance in macrophage polarization (elevated M1/M2 ratio). Pregnancy zone protein (PZP), a placent...
BACKGROUND: Preeclampsia (PE) is characterized by immune dysregulation at the maternal-fetal interface, particularly an imbalance in macrophage polarization (elevated M1/M2 ratio). Pregnancy zone protein (PZP), a placenta-derived immunomodulator, is dysregulated in PE, but its functional role and mechanism remain unclear. OBJECTIVE: To investigate the role and mechanism of trophoblast-derived PZP in regulating macrophage polarization and its contribution to PE pathogenesis. METHODS: Clinical samples from PE and control pregnancies were analyzed for PZP expression, macrophage subsets, TGF-β/Smad3 pathway activity, and inflammatory markers. In vitro, PZP was knocked down or overexpressed in HTR8/SVneo trophoblasts co-cultured with THP-1-derived macrophages; polarization, cytokines, and TGF-β pathway dependence were assessed. In vivo, placenta-specific Pzp knockdown was induced in pregnant mice via AAV9-shPzp, and PE-like phenotypes, macrophage polarization, inflammation, and TGF-β signaling were evaluated, with rescue by TGF-β1. RESULTS: PZP expression was significantly reduced in PE placentas, correlating negatively with disease severity and the M1/M2 ratio, and positively with pro-inflammatory cytokines. PZP localized to trophoblasts adjacent to macrophages. In vitro, PZP-deficient trophoblast conditioned media promoted M1 polarization (↑CD86, ↑IL-6/TNF-α, ↓CD206, ↓IL-10) and suppressed TGF-β/Smad3 signaling; these effects were significantly counteracted by PZP overexpression or exogenous TGF-β1 and blocked by TGF-β pathway inhibition. In vivo, placenta-specific Pzp knockdown induced hypertension, proteinuria, elevated placental M1/M2 ratio, and inflammation, associated with suppressed TGF-β/Smad3 signaling. TGF-β1 supplementation significantly ameliorated these phenotypes. CONCLUSION: Trophoblast-derived PZP deficiency contributes to immune dysregulation in PE by impairing TGF-β/Smad3 signaling, which disrupts M2 macrophage polarization and promotes a pro-inflammatory state at the maternal-fetal interface. PZP represents a promising therapeutic target and a potential placental tissue marker for PE, warranting further investigation into its utility for early risk stratification.
The dual roles of CD24 in tumorigenesis and immune evasion.
Yu H, Li Y, Wang Y … +2 more , Shi J, Hou Y
Mol Immunol · 2026 May · PMID 41950814 · Publisher ↗
CD24 is a glycosylphosphatidylinositol (GPI)-anchored protein overexpressed in multiple malignancies, where it drives tumor progression through diverse oncogenic signaling pathways. Beyond its established roles in promot...
CD24 is a glycosylphosphatidylinositol (GPI)-anchored protein overexpressed in multiple malignancies, where it drives tumor progression through diverse oncogenic signaling pathways. Beyond its established roles in promoting proliferation, metastasis, and immune evasion, emerging evidence reveals context-dependent functions including paradoxical tumor-suppressive effects in specific cancer subtypes. This review synthesizes current understanding of CD24's multifaceted contributions to tumorigenesis, examining its regulatory mechanisms, signaling networks, and therapeutic targeting strategies. We address critical unresolved questions regarding the integration of transcriptional and post-translational regulation with context-dependent oncogenic functions, the mechanistic bases for CD24's nuclear localization and paradoxical roles, and the therapeutic implications of targeting CD24-mediated immune evasion pathways.
A functional VCBP-C1q interaction in amphioxus reveals evolutionary origins of the classical complement pathway.
Gao J, Kang H, Wang L … +2 more , Wang H, Gao Z
Mol Immunol · 2026 May · PMID 41934766 · Publisher ↗
The origin of the classical complement pathway remains unclear, primarily due to the evolutionary interplay between immunoglobulin (Ig) and C1q. An Ig superfamily member, variable region-containing chitin-binding protein...
The origin of the classical complement pathway remains unclear, primarily due to the evolutionary interplay between immunoglobulin (Ig) and C1q. An Ig superfamily member, variable region-containing chitin-binding protein 5 (VCBP5), from the basal chordate amphioxus exhibited a marked upregulation upon E. coli stimulation and accumulated in the epithelial lining and circulatory sinuses of the hepatic caecum. Recombinant VCBP5 (rVCBP5) exhibits strong binding affinity for E. coli via the C'C'' loop of its IgV2 domain. Exogenous addition of rVCBP5 not only enhances the bactericidal activity of humoral fluids but also provides robust protection against bacterial proliferation in vivo. Notably, rVCBP5 specifically binds to the gC1q domain of BjC1q, with the interdomain hinge regions of VCBP5 serving as key interaction interfaces. Moreover, rBjC1q directly interacts with the serine protease BjMASP1/3. Importantly, formation of the VCBP5-bacterial complex facilitates rBjC1q-mediated recruitment of BjMASP1/3, thereby triggering complement activation. Our findings uncover a functional VCBP-C1q partnership in amphioxus, revealing a primitive complement activation pathway. This discovery provides new insights into the evolutionary emergence of the classical complement pathway.
FBXW11 regulates macrophage polarization and enhances the anti-tumor activity.
Zhang S, Li R, Xie W … +6 more , Cui X, Li Y, Zhao H, Ren Q, Wang L, Zheng G
Mol Immunol · 2026 May · PMID 41934765 · Publisher ↗
Macrophages can be polarized to various states in physiologic and pathologic microenvironments. The simplified but widely accepted M1/M2 polarization states play contradictory roles in tumor progression. The ubiquitin-pr...
Macrophages can be polarized to various states in physiologic and pathologic microenvironments. The simplified but widely accepted M1/M2 polarization states play contradictory roles in tumor progression. The ubiquitin-proteasome system (UPS), particularly F-box proteins, has been reported to be involved in immune regulation. However, the role of F-box and WD-40 domain protein 11 (FBXW11) on macrophage remains unclear. Here, the effects of FBXW11 on macrophage polarization and anti-tumor function were investigated. The results showed that FBXW11 promoted macrophage proliferation and induced a mild M1 polarization phenotype in the absence of tumor cells. Furthermore, overexpression of Fbxw11 enhanced the M1 polarization of macrophages in tumor co-culture system. Moreover, overexpression of Fbxw11 also enhanced glucose uptake and increased mitochondrial reactive oxygen species (ROS) levels, while reducing the mitochondrial membrane potential (Δψ) in macrophages in tumor co-culture system. Functionally, Fbxw11 overexpression increased the phagocytosis and killing of A20 lymphoma cells. RNA-sequencing analysis revealed that FBXW11 activated critical innate immune pathways, including JAK-STAT, NF-κB, and Toll-like receptor signaling, and upregulated effector molecules such as IL-6 and type I interferons. Collectively, our results reveal that FBXW11 paly a positive role on macrophage M1 polarization and anti-tumor function, which broaden the knowledge about how UPS modulates innate immunity.
The association of systemic immune-inflammation index with Th17/Treg imbalance, disease severity (PASI), and quality of life (DLQI/PLSI) in patients with psoriasis vulgaris: A cross-sectional study.
Lin L, Li W, Gao X … +7 more , Li Q, Zhou X, Liu W, Zhong X, Yang Y, Zhang X, Luo Q
Mol Immunol · 2026 May · PMID 41932288 · Publisher ↗
OBJECTIVE: This cross-sectional observational study aimed to investigate the relationship between systemic immune-inflammation index (SII) and Th17/Treg cell imbalance in psoriasis vulgaris (PV) at a specific timepoint (...
OBJECTIVE: This cross-sectional observational study aimed to investigate the relationship between systemic immune-inflammation index (SII) and Th17/Treg cell imbalance in psoriasis vulgaris (PV) at a specific timepoint (upon admission), as well as its predictive value for disease severity. METHODS: A total of 112 PV patients and 112 healthy controls were enrolled. Blood cell counts were used to calculate SII. Levels of Th17/Treg cells, cytokines (IL-17, IL-22, IL-10, TGF-β1), disease severity (PASI), and related factors were analyzed. Patients were classified into mild (MPV) or moderate-to-severe (MSPV) groups, and logistic regression identified independent risk factors for severity. RESULTS: PV patients showed elevated neutrophils, SII, Th17, IL-17, and IL-22, but reduced lymphocytes, Treg, IL-10, and TGF-β1. SII positively correlated with PASI. MSPV patients had higher BMI, SII, Th17/Treg ratio, and cytokines (P < 0.05). BMI, SII, and Th17/Treg ratio were independent predictors of severity. CONCLUSION: This cross-sectional study indicates significant correlations of elevated SII levels in PV patients at a specific timepoint (upon admission) with Th17/Treg imbalance, disease severity (PASI), and poorer quality of life (DLQI/PLSI). These findings suggest the possibility of SII at a specific timepoint (upon admission) as a "snapshot" biomarker of the immuno-inflammatory status in PV.
CYR61 promotes obesity-induced kidney injury by activating endoplasmic reticulum stress.
Li B, Lv H, Gong K … +3 more , Gao Y, Zhen J, Hu Z
Mol Immunol · 2026 May · PMID 41855765 · Publisher ↗
The objective was to assess the influence of cellular communication network factor 1 (CYR61) in obesity-induced kidney damage, as well as its potential mechanisms. An obesity-induced kidney damage was established in rats...
The objective was to assess the influence of cellular communication network factor 1 (CYR61) in obesity-induced kidney damage, as well as its potential mechanisms. An obesity-induced kidney damage was established in rats using a high-fat diet (HFD), and human proximal tubule epithelial (HK-2) cells were treated with palmitic acid (PA) for an in vitro model. Biochemical analysis was performed using test kits. The influence of CYR61 on kidney damage were evaluated by HE staining, periodic acid-Schiff staining, Masson's trichrome staining and western blot. The effect of CYR61 on cell apoptosis in vitro was assessed employing flow cytometry. The influence of CYR61 on lipid accumulation in vitro was assessed by Oil red O staining. Besides, the protein and mRNA expression levels were determined via western blot, immunohistochemistry, immunofluorescence and qRT-PCR. CYR61 was upregulated in rats with HFD-induced kidney injury and PA-treated HK-2 cells. CYR61 knockdown ameliorated metabolic parameters, kidney injury, oxidative stress, apoptosis, and inflammation, while suppressing endoplasmic reticulum (ER) stress in rats with HFD-induced kidney damage. CYR61 knockdown inhibited apoptosis, inflammation, oxidative stress, lipid accumulation and ER stress in the PA-treated HK-2 cells; however, tunicamycin reversed these inhibitory effects. These findings confirmed that CYR61 knockdown could ameliorated oxidative stress and inflammation in PA-treated HK-2 cells and HFD-induced renal damage in rats by suppressing ER stress.
The role of macrophages in the immune microenvironment of splenic ectopic pregnancy.
Li L, Kang M, Chen S … +6 more , Lu X, Song Y, Li H, Wang T, Jia C, Xu C
Mol Immunol · 2026 May · PMID 41825266 · Publisher ↗
Splenic ectopic pregnancy is a rare and life-threatening condition, with no prior studies exploring its immune microenvironment. We analyzed immune cell alterations in splenic ectopic pregnancy and the potential role of...
Splenic ectopic pregnancy is a rare and life-threatening condition, with no prior studies exploring its immune microenvironment. We analyzed immune cell alterations in splenic ectopic pregnancy and the potential role of macrophages in pregnancy using immunohistochemical staining, transcriptomic profiling, and histological analysis. Our findings suggest that M2 macrophages may play a crucial role in maintaining successful pregnancy. The biological effects of macrophages on trophoblast cells were evaluated through CCK-8, migration, and invasion assays. Our results demonstrated that in splenic ectopic pregnancy tissues, significant reductions in CD20 B cells, CD8 T cells, and CD86 M1 macrophages were observed within splenic regions, while CD206 M2 macrophages were markedly increased in areas of trophoblast cell infiltration. This predominance of M2 macrophages may promote embryonic survival in splenic ectopic implantation. Transcriptomic and histological analyses of endometrial tissues from recurrent miscarriage (RM) patients revealed comparable M1/M2 macrophage dysregulation. In vitro experiments further demonstrated that M2 macrophages significantly enhanced trophoblast cell migration and invasion via PDGFR-β and PI3K-AKT-mTOR pathway. This study is the first to analyze the immune microenvironment of splenic ectopic pregnancy, revealing the critical role of M2 macrophages in maintaining normal immune tolerance.
FNDC4 modulates macrophage responses and suppresses NF-κB in sepsis-induced lung injury.
Chen J, Li J, Huang Y … +7 more , Fan Y, Li W, Ye J, Liu G, Jiang B, Pan S, Gao C
Mol Immunol · 2026 May · PMID 41819760 · Publisher ↗
Regulation of pulmonary macrophages and their related functions is crucial for preventing further deterioration in many diseases. Fibronectin III domain-containing 4 (FNDC4) is a secreted factor with high homology to the...
Regulation of pulmonary macrophages and their related functions is crucial for preventing further deterioration in many diseases. Fibronectin III domain-containing 4 (FNDC4) is a secreted factor with high homology to the exercise-related myokine irisin (FNDC5) and has been reported to be significantly upregulated in multiple mouse models of inflammation and under human inflammatory conditions. Here, we investigated the role and mechanisms of FNDC4 in regulating pulmonary macrophage function and the NF-κB pathway in sepsis. Plasma samples and clinical data from sepsis patients and healthy volunteers were collected to quantify FNDC4 levels and analyze their association with sepsis severity. In vivo, septic rat models with different disease severities were established to evaluate the effects of FNDC4 on lung injury. In vitro, LPS-stimulated mouse macrophages (RAW264.7) were preincubated with varying concentrations of FNDC4 to explore its functional effects and underlying mechanisms. Clinically, plasma FNDC4 levels were lower in sepsis patients than in healthy controls and were positively correlated with sepsis severity. In animal experiments, FNDC4 administration effectively alleviated sepsis-induced lung injury. In cell-based assays, FNDC4 preserved the proliferation and migration of LPS-stimulated RAW264.7 cells and reduced their apoptosis rate, while also inhibiting phosphorylation-dependent activation within the NF-κB pathway. Collectively, these findings suggest that FNDC4 may reflect sepsis severity and that exogenous FNDC4 can mitigate sepsis-related lung damage in vivo, potentially through modulation of the NF-κB signaling pathway, indicating its potential therapeutic value in sepsis.
m⁶A-modified circMELK regulates nasopharyngeal carcinoma progression via a YTHDF1/circMELK-miR-4775-HMGA2 feedback loop.
Yi Q, Zhong K, Chen Z … +4 more , Ouyang X, Zhu W, Liang L, Zhong J
Mol Immunol · 2026 May · PMID 41812494 · Publisher ↗
BACKGROUND: Circular RNAs (circRNAs) are emerging regulators in tumor biology. However, their roles in nasopharyngeal carcinoma (NPC) remain poorly defined. METHODS: By analyzing GSE190271, we identified hsa_circ_0138742...
BACKGROUND: Circular RNAs (circRNAs) are emerging regulators in tumor biology. However, their roles in nasopharyngeal carcinoma (NPC) remain poorly defined. METHODS: By analyzing GSE190271, we identified hsa_circ_0138742 (circMELK) as significantly upregulated in NPC. Functional assays in vitro and in vivo were performed to explore its biological role. Mechanistic studies included RIP, ChIP, RNA pull-down, dual-luciferase assays, and rescue experiments. RESULTS: circMELK was markedly elevated in NPC tissues and cells. Silencing circMELK inhibited NPC cell proliferation, migration, and invasion, while overexpression enhanced these malignant traits. Mechanistically, YTHDF1-mediated m6A modification serves as a key determinant for the cytoplasmic export of circMELK. There, circMELK acts as a ceRNA for miR-4775, relieving suppression of HMGA2. Elevated HMGA2 upregulates YTHDF1 by transcriptional activation, forming a YTHDF1/circMELK-miR-4775-HMGA2 positive feedback loop that drives epithelial-mesenchymal transition (EMT) and promotes metastasis. CONCLUSION: circMELK promotes NPC progression via a novel m6A-dependent ceRNA regulatory loop. Targeting this axis may offer new therapeutic opportunities.
Phillyrin attenuates TGF-β1-induced pulmonary fibrosis by modulating the Nrf2/HO-1 pathway and epithelial-mesenchymal transition.
Yu J, Liu Y, Song H … +11 more , Liu L, Li L, Luo Y, Ma Y, Zhu R, Liu X, Xia S, Zhang D, Meng J, Li W, Niu X
Mol Immunol · 2026 May · PMID 41812493 · Publisher ↗
BACKGROUND: Phillyrin (Phi), a natural lignan glycoside derived from Fructus Forsythiae, has been reported to exhibit anti-inflammatory and antioxidant activities. In this study, we investigated its therapeutic potential...
BACKGROUND: Phillyrin (Phi), a natural lignan glycoside derived from Fructus Forsythiae, has been reported to exhibit anti-inflammatory and antioxidant activities. In this study, we investigated its therapeutic potential in a TGF-β1-induced model of epithelial-mesenchymal transition (EMT) in A549 human alveolar epithelial cells. METHODS: The mechanisms of Phi were initially predicted using network pharmacology and molecular docking. Subsequently, A549 cells were stimulated with TGF-β1 and treated with Phi. Key assessments included cell viability, inflammatory and oxidative stress markers, EMT-related proteins (E-cadherin, α-SMA, vimentin), and fibrosis-associated molecules (collagen I, fibronectin, MMP-2). The activation of the Nrf2/HO-1 antioxidant pathway was also examined. RESULTS: Phi significantly attenuated TGF-β1-induced EMT and fibrotic responses in A549 cells. It not only suppressed inflammatory cytokine production and oxidative stress but also restored epithelial marker expression and reduced mesenchymal and fibrotic protein levels. Moreover, Phi upregulated the Nrf2/HO-1 signaling pathway, enhancing cellular antioxidant capacity. CONCLUSION: These findings suggest that Phi possesses potent anti-inflammatory, antioxidant, and anti-fibrotic properties, effectively inhibiting TGF-β1-driven EMT in alveolar epithelial cells. Phi may represent a promising therapeutic candidate for treating idiopathic pulmonary fibrosis and other fibrotic lung diseases.
Mechanistic study of swertiamarin in treating ulcerative colitis by regulating YAP-mediated Wnt and Notch pathways for intestinal stem cell repair.
Chen J, Peng H, Chen J … +2 more , Liu Y, Chen L
Mol Immunol · 2026 May · PMID 41806558 · Publisher ↗
BACKGROUND: Ulcerative colitis (UC) is a chronic immune-mediated inflammatory disease. In 2024, the American Gastroenterological Association updated its guidelines for UC patients, shifting the treatment goal from "clini...
BACKGROUND: Ulcerative colitis (UC) is a chronic immune-mediated inflammatory disease. In 2024, the American Gastroenterological Association updated its guidelines for UC patients, shifting the treatment goal from "clinical remission" to "mucosal healing" and "histological healing." This highlights the vital role of the interaction between intestinal stem cells (ISCs) and immune cells in maintaining and repairing intestinal tissue homeostasis. However, effective regulatory approaches targeting ISC-immune crosstalk are lacking in current clinical practice. The traditional Chinese medicine Qinjiao, which is widely used in clinical prescriptions for treating UC, contains many iridoid compounds, but whether they can promote tissue healing by regulating the ISC immune microenvironment remains to be clarified. METHODS: UHPLC-MS and an ISC injury organoid model were applied to identify and screen the four major iridoid compounds in Qinjiao. Then, the pharmacodynamic effects of swertiamarin (SW) on UC mice, the proliferation and differentiation of colonic ISCs, and the related status of Wnt, Notch, and Hippo-YAP signaling pathways were analyzed using RT-qPCR and other methods. Finally, the mechanism in organoids was verified using the YAP inhibitor Verteporfin. RESULTS: This study found that SW, a bioactive iridoid compound from Qinjiao, alleviated weight loss, mitigated colon atrophy, and reduced DAI scores in UC mice. SW also restored the proliferation and differentiation of ISCs. It mitigated immune-inflammatory responses and repaired the mucosal barrier by modulating YAP nuclear translocation to activate Wnt/β-catenin signaling and downregulate Notch signaling, enhancing ISC proliferation and differentiation. CONCLUSION: This study revealed that iridoid compounds, represented by SW, are the primary active components in Qinjiao for treating UC by restoring mucosal barrier integrity through enhanced ISC proliferation and differentiation.
Emerging molecular mechanisms of cGAS-STING activation and regulation.
Liu Y, Ma K, Jiang Z
Mol Immunol · 2026 May · PMID 41806557 · Publisher ↗
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a crucial component of the innate immune system, responsible for detecting cytosolic double-stranded DNA (dsDNA) from both pa...
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a crucial component of the innate immune system, responsible for detecting cytosolic double-stranded DNA (dsDNA) from both pathogen invasion and host damage, thereby initiating a robust type I-interferons (IFNs) response. In this review, we summarize the complex and stringent mechanisms governing the activation and regulation of the cGAS-STING pathway. We describe the structural basis of cGAS activation by dsDNA and its catalytic synthesis of 2'3'-cGAMP, and highlight the DNA-independent activation of cGAS by manganese (Mn), which exhibits a distinct catalytic mechanism. We also discuss recent advances in the regulatory mechanisms of cGAS. The binding of 2'3'-cGAMP triggers STING translocation from the ER to the Golgi apparatus, where sulfated glycosaminoglycans (sGAGs) act as an essential second ligand to promote STING polymerization. Following this, a second translocation from the trans-Golgi network (TGN) to endosomes is required for its full activation. Conversely, supranormal concentrations of 2'3'-cGAMP induce the formation of ER-localized STING biocondensates, which restrict activation and thus prevent an excessive immune response. Dysregulation of the cGAS-STING pathway has been implicated in diverse human health conditions, including infection, autoimmune disorders, neurodegeneration, ageing, and cancer. Understanding these activation and regulatory mechanisms will inform the development of novel therapeutic strategies.
vtRNA1-1/p62 regulates macrophages autophagy in ankylosing spondylitis.
Jiang M, Ni J, Yu X … +11 more , Zhao H, Lu X, Cheng L, Li Z, Wu H, Pan Z, Qu L, Gao M, Cai G, Wang M, Pan F
Mol Immunol · 2026 May · PMID 41795403 · Publisher ↗
This research aims to investigate the role and mechanisms of the vtRNA1-1/p62 molecular axis in the regulation of autophagy in AS, with the goal of identifying novel diagnostic and therapeutic targets for AS. Clinical sa...
This research aims to investigate the role and mechanisms of the vtRNA1-1/p62 molecular axis in the regulation of autophagy in AS, with the goal of identifying novel diagnostic and therapeutic targets for AS. Clinical sample analysis revealed that the transcription levels of vtRNA1-1 and p62 decreased in the peripheral blood mononuclear cells (PBMCs) of the AS group; conversely, the levels of canonical autophagy-related genes (ATG3, ATG5) and inflammatory factors (TNF-α) significantly increased. Correlation analysis revealed that vtRNA1-1 levels were positively associated with p62 but were inversely associated with ATG3, ATG5, and TNF-α. In vitro cell experiments demonstrated that vtRNA1-1 depletion reduced p62 expression while increasing ATG3, ATG5, and LC3B levels. Computational modeling further confirmed significant interactions between vtRNA1-1 and p62. Notably, vtRNA1-1 and p62 demonstrated unique diagnostic value for AS, with their combination showing even greater diagnostic significance. This study innovatively links noncoding RNA regulatory networks with autophagy homeostasis imbalance, revealing that vtRNA1-1 may regulate macrophage autophagy through p62, thereby participating in the molecular pathogenesis of AS.
Navigating the frontier of CAR-T cell resistance: From underlying mechanisms to innovative therapeutic solutions.
Lan F, Song J, Chen X … +1 more , Zhang Y
Mol Immunol · 2026 Apr · PMID 41791174 · Publisher ↗
Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of relapsed or refractory hematological malignancies, particularly acute B-cell lymphoblastic leukemia (B-ALL), B-cell lymph...
Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of relapsed or refractory hematological malignancies, particularly acute B-cell lymphoblastic leukemia (B-ALL), B-cell lymphoma (BCL), and multiple myeloma (MM). However, resistance in hematological malignancies and limited immune responses in solid tumors remain major challenges for CAR-T cell therapy. Tumor antigen loss or modulation, dysregulated apoptotic signaling, CAR-T cell-intrinsic dysfunction, and immunosuppressive components within the tumor microenvironment (TME) significantly compromise therapeutic outcomes. Therefore, understanding the mechanisms that mediate resistance to CAR-T cell therapy and exploring strategies to overcome therapeutic failure are crucial for optimizing clinical results. This review systematically elucidates the mechanisms underlying resistance to CAR-T cell therapy and discusses potential countermeasures, including dual-targeted approaches, innovative CAR engineering strategies, TME reprogramming, and combination immunotherapies.
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