Cellular & Molecular Immunology[JOURNAL]
Sun
200 papers
Transcriptomic sequencing analysis of the tumor microenvironment atlas and potential mechanisms of metastasis in papillary thyroid carcinoma.
An H, Zhang W, Niu H … +6 more , Liang W, Lv B, Wu S, Xu L, Li W, Gao S
Mol Immunol · 2026 Jul · PMID 42134246 · Publisher ↗
Papillary thyroid carcinoma (PTC) is the most prevalent thyroid malignancy and its incidence continues to rise. Although prognosis is generally favorable, overdiagnosis, overtreatment, and occasional lethal complications...
Papillary thyroid carcinoma (PTC) is the most prevalent thyroid malignancy and its incidence continues to rise. Although prognosis is generally favorable, overdiagnosis, overtreatment, and occasional lethal complications persist. To clarify the micro-environmental basis of PTC metastasis, we integrated single-cell RNA-seq from tumor (T), peritumoral thyroid (PT) and lymph-node (LN) tissues with bulk transcriptomes. Metastatic (M) and non-metastatic (NM) cases were compared, and machine-learning models were built to predict lymph-node status and outcome. Our atlas delineates highly heterogeneous ecosystems across T, PT and LN samples. Within T/NK lymphocytes, both immune-activating and immune-suppressive subsets coexist; NK and CD4+TNFRSF4 cells were selectively enriched in M tumors, implying heterogeneous anti-tumor responses. Among myeloid cells, a Mac-APOC1 subset displayed tumor-associated macrophage/M2 features, consistent with immune escape and dissemination. Dendritic cells differed markedly in antigen presentation and chemotaxis, while RGS5+ myCAFs, markedly expanded in M samples from T and LN, up-regulated metabolic and ribosomal pathways. Trajectory analysis uncovered dynamic CAF state transitions. Tumor epithelial cells followed multiple developmental branches, with those linked to LN invasion predicting poorer survival. A random-forest classifier achieved 0.98 accuracy for N-stage, and a lasso-Cox signature (C-index > 0.9) robustly stratified survival, underscoring the clinical relevance of the identified genes. Collectively, this work reveals the cellular and functional heterogeneity that drives PTC progression, identifies metastasis-associated subpopulations, and demonstrates the utility of machine learning for precise prediction of lymph-node metastasis and patient prognosis, offering a foundation for tailored therapeutic strategies.
CBL proto-oncogene C-mediated synaptophysin 1 regulates prostate cancer progression in the TGF-beta signalling pathway.
Tong J, Hu L, Liu Q … +1 more , Tian D
Mol Immunol · 2026 Jul · PMID 42119245 · Publisher ↗
OBJECTIVE: This study aims to screen and validate the differentially expressed gene synaptophysin 1 (SYT1), which plays a key regulatory role in prostate cancer, explore its function and potential regulatory mechanisms,...
OBJECTIVE: This study aims to screen and validate the differentially expressed gene synaptophysin 1 (SYT1), which plays a key regulatory role in prostate cancer, explore its function and potential regulatory mechanisms, and clarify its biological role and molecular mechanisms in the malignant progression of prostate cancer. METHODS: Differential expression analysis was performed using the GEO database dataset GSE69223, combined with the TIMER and UALCAN databases to validate the expression levels and prognostic value of the candidate gene SYT1. To further ensure the biological plausibility of the results, this study selected cell lines representing different prostate cancer subtypes and disease stages, including the normal epithelial cell line RWPE-1, the adenocarcinoma-like AR⁺ cell line LNCaP, the basal-like/AR⁻ cell line PC3, and the neuroendocrine cell line NCI-H660, and assessed differences in SYT1 expression using qRT-PCR and Western blot analysis. SYT1-overexpressing cell lines were established, and their effects on prostate cancer cell proliferation, migration, and invasion were assessed using EDU, colony formation, scratch, and Transwell assays. Using UbiBrowser, we predicted potential E3 ubiquitin ligases for SYT1 and screened CBL proto-oncogene C (CBLC) as a candidate upstream regulatory factor through differential analysis. We validated the regulatory role of CBLC in SYT1 ubiquitination and degradation via immunoprecipitation experiments and explored its mechanism of action through functional interaction experiments and signalling pathway analysis. RESULTS: SYT1 is significantly downregulated in prostate cancer tissues, and its downregulation is associated with poor prognosis in prostate cancer. Overexpression of SYT1 significantly inhibits the proliferation, migration, and invasion of prostate cancer cells. CBLC is highly expressed in prostate cancer and promotes the ubiquitination and degradation of SYT1. Knocking down CBLC reduces the ubiquitination level of SYT1 and stabilises its protein expression. Overexpression of CBLC partially reverses the antitumour effects mediated by SYT1. Mechanistic studies indicate that SYT1 exerts its antitumour function by inhibiting the TGF-β/SMAD signalling pathway, while CBLC interferes with this pathway by promoting its degradation. CONCLUSION: Prostate cancer may have SYT1 as a tumor suppressor gene, and the E3 ligase CBLC regulates its ubiquitin-mediated degradation. SYT1 inhibits tumour progression by suppressing the TGF-β/SMAD signalling pathway, while CBLC promotes the malignant development of prostate cancer by negatively regulating SYT1.
CSF1R signaling contributes to macrophage-associated CCL11 production and eosinophil recruitment in murine allergic conjunctivitis.
Du J, Wu J, Tan X … +8 more , Xie J, Zhuang Z, Lan H, Xue Y, Fu T, Gu J, Li Z, Liu J
Mol Immunol · 2026 Jul · PMID 42105679 · Publisher ↗
Allergic conjunctivitis (AC) is a prevalent ocular surface inflammatory disorder with limited therapeutic options. In this study, we investigated the role of colony-stimulating factor 1 receptor (CSF1R) in an ovalbumin (...
Allergic conjunctivitis (AC) is a prevalent ocular surface inflammatory disorder with limited therapeutic options. In this study, we investigated the role of colony-stimulating factor 1 receptor (CSF1R) in an ovalbumin (OVA)-induced murine model of AC. Conjunctival expression of CSF1R and its ligands, interleukin-34 (IL-34) and colony-stimulating factor 1 (CSF1), was significantly upregulated following OVA challenge. Pharmacological inhibition of CSF1R with BLZ945 alleviated clinical symptoms, reduced the infiltration of CD45⁺ leukocytes and eosinophils, and attenuated an M2-associated macrophage phenotype in the conjunctiva. Similar suppression of eosinophil infiltration was observed with a second CSF1R inhibitor, AZD7507. In addition, conjunctival CD206⁺ macrophages with an M2-associated phenotype expressed C-C motif chemokine ligand 11 (CCL11), which was elevated in AC and downregulated by CSF1R inhibition. Recombinant CCL11 significantly restored eosinophil infiltration in BLZ945-treated mice, supporting a role for CCL11 as a downstream effector of CSF1R signaling in this model. Collectively, these findings support a contributory role for CSF1R signaling in macrophage-associated eosinophilic inflammation in murine AC and suggest that targeting CSF1R may represent a potential therapeutic strategy for ocular allergic disease.
Acupuncture enhances warm kidney and spleen granules efficacy in diabetic diarrhea through synergistic p300/CBP inhibition and Nrf2/HO-1 pathway activation.
Wang Z, Li X, Tan Y … +4 more , Wang Y, Deng Y, Liu Y, Liu D
Mol Immunol · 2026 Jul · PMID 42105678 · Publisher ↗
Diabetic diarrhea (DD), affecting ∼20% of diabetic patients, lacks effective pharmacological treatment. This study investigates Warm Kidney and Spleen Granules (WKSG) combined with acupuncture for treating DD, focusing o...
Diabetic diarrhea (DD), affecting ∼20% of diabetic patients, lacks effective pharmacological treatment. This study investigates Warm Kidney and Spleen Granules (WKSG) combined with acupuncture for treating DD, focusing on p300/CBP-H3K27ac pathway and antioxidant/inflammatory signaling mechanisms. Male Wistar rats with HFD/STZ-induced DD received WKSG (1 g/day, 14 days), acupuncture (daily for 4 weeks; seven acupoints), or combined therapy over 35 days. Additional diabetic rats and high-glucose-stimulated Caco-2 cells were used for mechanistic validation of p300/CBP pathway involvement through p300 overexpression/silencing and pharmacological activation with CTPB. Clinical parameters such as body weight, fasting blood glucose, defecation frequency, and fecal moisture content were assessed weekly. Intestinal permeability was evaluated via transepithelial electrical resistance (TEER) and in vivo FITC-dextran permeability. Tight junction proteins (ZO-1/occludin), oxidative stress markers (ROS/MDA/SOD/GSH), p300/CBP-H3K27ac expression, Nrf2/HO-1 activation, NF-κB phosphorylation, and inflammatory cytokines (TNF-α/IL-6) were measured by Western blotting, qPCR, and ELISA. Mechanistic causality was established using p300 overexpression (oe-p300) and silencing (si-p300) lentiviral vectors in both animals and high-glucose-stimulated Caco-2 intestinal epithelial cells. Epithelial apoptosis was assessed by flow cytometry. STZ-treatment elevated colonic p300/CBP-H3K27ac, oxidative stress, inflammatory cytokines, and intestinal permeability while reducing body weight, tight junction proteins, and antioxidant enzymes. WKSG suppressed p300/CBP-HAT activity, reduced ROS/MDA, restored SOD/GSH, activated Nrf2/HO-1, inhibited NF-κB and TNF-α/IL-6, and restored barrier function; these effects were reversed by p300 overexpression. In Caco-2 cells, WKSG suppressed p300/CBP-mediated H3K27ac acetylation. Combined acupuncture and WKSG synergistically enhanced all parameters beyond monotherapy, reducing apoptosis rates further. Overall, WKSG ameliorates DD through p300/CBP inhibition, activating Nrf2/HO-1 antioxidant defense and suppressing NF-κB-mediated inflammation. Acupuncture synergistically amplifies efficacy, establishing mechanistic rationale for integrated therapy in DD management.
The CLEC-2-podoplanin axis inhibits dendritic cells migration and prolongs allograft survival in mice.
Wang H, Zhang H, Ye D … +6 more , Zhang L, Zhang X, Wang S, Ju W, Gao Y, Ma Y
Mol Immunol · 2026 Jul · PMID 42102414 · Publisher ↗
BACKGROUND: Dendritic cell (DC) migration-triggered T cell activation is a pivotal event in transplant rejection. Previous studies have established a critical role of the C-type lectin receptor 2（CLEC-2）and podoplanin...
BACKGROUND: Dendritic cell (DC) migration-triggered T cell activation is a pivotal event in transplant rejection. Previous studies have established a critical role of the C-type lectin receptor 2（CLEC-2）and podoplanin (PDPN) axis in regulating DC migration. We therefore hypothesized that targeting CLEC-2-PDPN axis could prolong allograft survival in mice by impairing DC migration. MATERIALS AND METHODS: Bioinformatics analysis was performed to assess differential CLEC-2 expression between allograft and isograft tissues and to identify potential associated biological processes. Bone marrow-derived dendritic cells (BMDCs) were generated from donor mice and treated with anti-CLEC-2 to inhibit CLEC-2 function. After LPS stimulation, surface expression of costimulatory molecules and MHC class II, as well as phagocytic capacity, were analyzed. Migration in response to PDPN and CCL19 gradients and the ability to stimulate T cell proliferation were evaluated using a Transwell assay. A murine skin allograft model (BALB/c to C57BL/6) was established. Then anti-PDPN was injected into recipient mice during transplantation. Graft survival was monitored, and pathological examination of grafts, flow cytometric analysis of draining lymph nodes (assessing DC migration and T cell activation/proliferation), and serum cytokine detection by ELISA were performed. RESULTS: Bioinformatics analysis revealed that CLEC-2 was significantly upregulated in the allograft group. In vitro, CLEC-2 suppression had no significant effect on the expression of costimulatory molecules or phagocytosis in dendritic cells. However, it specifically inhibited PDPN-mediated migration and suppressed T cell proliferation in the Transwell assay. Anti-PDPN treatment significantly prolonged skin allograft survival and attenuated rejection in mice. Flow cytometry revealed a reduced proportion of migratory DCs, particularly of the cDC2 subset in the draining lymph nodes of treated mice. Furthermore, both CD4 + and CD8 +T cell proliferation and activation were markedly suppressed. ELISA results showed decreased serum levels of IL-18 and IL-1β, while elevated IL-10. CONCLUSION: Targeting the CLEC-2-PDPN axis significantly prolongs murine allograft survival via the inhibiting DC migration and subsequent T-cell proliferative responses.
Edwardsiella piscicida effector VgrG contributes to NCOA4-dependent ferritinophagy as a bacterial survival strategy in fish.
Xiong D, Liu J, Wang Z … +2 more , Ma X, Zhou H
Mol Immunol · 2026 Jul · PMID 42102413 · Publisher ↗
Edwardsiella piscicida is an intracellular bacterial pathogen that causes intestinal injury and hemorrhagic sepsis in marine and freshwater animals. VgrG (valine-glycine repeat protein G) has been identified as a crucial...
Edwardsiella piscicida is an intracellular bacterial pathogen that causes intestinal injury and hemorrhagic sepsis in marine and freshwater animals. VgrG (valine-glycine repeat protein G) has been identified as a crucial virulence factor in the type VI secretion system (T6SS) of the bacterium, but its role and mechanism involved in E. piscicida-host interactions remain unclear. In this study, we found that the wild-type E. piscicida strain markedly induced host cell ferritin degradation and elevated intracellular Fe²⁺ levels, but a vgrG deletion mutant (ΔvgrG) strain failed to induce similar effects in fish cells, indicating the role of VgrG in the regulation of iron metabolism. However, in the NCOA4 (nuclear receptor coactivator 4, a selective cargo receptor that binds ferritin)-knockout fish cells, VgrG did not alter ferritin protein expression and E. piscicida-promoted intracellular Fe²⁺ levels, suggesting that VgrG caused iron storage disorders via NCOA4-dependent ferritinophagy. In support of this notion, VgrG overexpression was found to facilitate the co-localization of ferritin with autophagosomes and lysosomes, and also drove the interaction of NCOA4 with lysosomes, strengthening the involvement of this effector in mediating NCOA4-dependent ferritinophagy. Notably, in NCOA4-knockout cells, the inhibitory effect of VgrG on the intracellular growth of E. piscicida was further magnified, particularly highlighting the role of VgrG-induced ferritinophagy in augmenting bacterial intracellular survival. Moreover, zebrafish infected with the ΔvgrG strain had a much higher survival rate than those infected with the wild-type strain. In summary, our data revealed a new function of VgrG in maintaining the persistence of E. piscicida within host cells, which advanced our understanding of how intracellular pathogens target ferritinophagy to evade the host's immune surveillance. Moreover, this work also supported the potential for developing defense strategies against E. piscicida based on the VgrG-induced ferritinophagy response in fish.
PIAS1 attenuates the progression of abdominal aortic aneurysm by stabilizing PPARγ through SUMOylation.
Wang H, Dai R, Wang J … +4 more , Wu K, Yang B, Feng Y, Zhao L
Mol Immunol · 2026 Jul · PMID 42102412 · Publisher ↗
BACKGROUND AND PURPOSE: Protein inhibitor of activated STAT 1 (PIAS1) functions as a SUMO E3 ligase, regulating cardiovascular diseases by promoting the SUMOylation of target proteins; however, its role in abdominal aort...
BACKGROUND AND PURPOSE: Protein inhibitor of activated STAT 1 (PIAS1) functions as a SUMO E3 ligase, regulating cardiovascular diseases by promoting the SUMOylation of target proteins; however, its role in abdominal aortic aneurysm (AAA) remains unclear. Currently, molecular targeted therapies for AAA are still very limited. This study aimed to clarify whether PIAS1 regulates the stability of the PPARγ protein through SUMOylation to elucidate its molecular mechanisms in AAA formation and to evaluate its potential as a novel therapeutic target. METHODS: AAA rat models were established via the infusion of porcine pancreatic elastase, and an in vitro cell model was constructed by treating human umbilical vein endothelial cells (HUVECs) with Ang II. Flow cytometry, ELISA, H&E staining, and EVG staining were used to assess cell and abdominal aortic tissue damage, while RT-qPCR and Western blotting were used to detect the expression of relevant genes and proteins. RESULTS: This study revealed that PIAS1 is expressed at low levels in AAA. The overexpression of PIAS1 effectively inhibited Ang II-induced lipid accumulation and inflammatory responses in HUVECs and AAA rats, alleviated pathological damage and apoptosis in the abdominal aorta, and alleviated the progression of AAA. With respect to the regulatory mechanism, the SUMOylation and expression levels of PPARγ are downregulated in AAA. PIAS1 primarily stabilizes PPARγ expression by promoting its SUMOylation, thereby inhibiting lipid accumulation and inflammatory responses. Further studies revealed that SENP3 is highly expressed in AAA and that PIAS1 can downregulate SENP3 levels, thereby attenuating its deSUMOylation effect on PPARγ and ultimately promoting the SUMOylation and expression of PPARγ. CONCLUSION: PIAS1 alleviates the progression of AAA by inhibiting SENP3 expression, thereby promoting PPARγ SUMOylation and protein expression, which in turn reduces lipid accumulation and inflammatory responses.
Promoting keratinocyte psoriasiform changes and IL-17RE expression: Potential role of GLT1D1 in linear psoriasis.
Cheng Y, Chen L, Lin J … +4 more , Peng L, Xiong H, Liu G, Shen Z
Mol Immunol · 2026 Jul · PMID 42090972 · Publisher ↗
BACKGROUND: Linear psoriasis is a rare variant of psoriasis characterized by erythema and scaling along the Blaschko lines. Its pathogenesis remains unknown. OBJECTIVE: To investigate the molecular and immunological mech...
BACKGROUND: Linear psoriasis is a rare variant of psoriasis characterized by erythema and scaling along the Blaschko lines. Its pathogenesis remains unknown. OBJECTIVE: To investigate the molecular and immunological mechanisms of linear psoriasis through gene mutation analysis and in vitro experiments and identify potential combined therapeutic targets for psoriasis. METHODS: Whole-exome sequencing was performed on linear lesion, clinically normal skin, and peripheral blood from linear psoriasis patient to identify somatic mutations. Candidate gene expression was assessed using public RNA-seq data of linear and classic psoriasis vulgaris, dataset before and after IL-17 antagonist Brodalumab treatment, and single-cell data of recurrent psoriasis lesions. Immunofluorescence staining confirmed gene expression and distribution. In vitro keratinocyte assays evaluated effects on proliferation and inflammation. Based on these findings, the patient received IL-17 antagonist therapy (Ixekizumab). RESULTS: An increased copy number variant of Glycosyltransferase 1 Domain Containing 1 (GLT1D1), not previously reported, was identified in the epidermis of linear psoriasis. GLT1D1 was highly expressed in both linear psoriasis and classic psoriasis vulgaris, as well as in recurrent lesions and in patients who failed to achieve PASI75 with IL-17 antagonist therapy. In keratinocytes, GLT1D1 overexpression promoted cell proliferation, enhanced proinflammatory cytokine secretion, and activated IL-17 signaling, particularly via IL-17RE upregulation. In imiquimod-induced mouse models, GLT1D1 overexpression aggravated psoriasiform inflammation. Clinical improvement was observed in the patient after treatment with ixekizumab. CONCLUSION: GLT1D1, with an abnormally high copy number, may contribute to psoriasiform changes in keratinocytes by promoting proliferation, increasing proinflammatory cytokine secretion, and enhancing IL-17RE expression.
Quercetin attenuates LTA-induced tight junction disruption in mammary epithelial cells by modulating autophagy via the AMPK/mTOR pathway.
Song L, Li X, Wang L … +2 more , Liu J, Xiao L
Mol Immunol · 2026 Jul · PMID 42090971 · Publisher ↗
Mastitis in dairy cows impairs lactation and limits the development of the dairy industry. Lipoteichoic acid (LTA), a virulence factor of Staphylococcus aureus, disrupts the blood-milk barrier in the mammary gland. Querc...
Mastitis in dairy cows impairs lactation and limits the development of the dairy industry. Lipoteichoic acid (LTA), a virulence factor of Staphylococcus aureus, disrupts the blood-milk barrier in the mammary gland. Quercetin, known for its anti-inflammatory and antibacterial properties, was evaluated for its protective effects against LTA-induced tight junction (TJ) injury. We established a TJ injury model using LTA-treated MAC-T cells (a mammary epithelial cell line) and mouse mammary tissue. Results demonstrated that LTA compromised TJ integrity and induced dysregulated autophagy in MAC-T cells. Notably, quercetin treatment was associated with the inhibition of this autophagic dysregulation and attenuated the LTA-induced disruption of TJ protein expression. Further mechanistic studies revealed that both quercetin and Compound C (CC, an AMPK inhibitor) reduced autophagy levels and mitigated the LTA-induced decline in key TJ proteins, suggesting that quercetin is associated with the attenuation of LTA-induced TJ integrity disruption under inflammatory stress, which correlates with modulated changes in AMPK phosphorylation and the mTOR signaling pathway. In vivo mouse experiments confirmed that quercetin acts as a dual-action modulator that regulates baseline signaling while attenuating LTA-induced TJ protein damage. This protective process is mediated through the modulation of AMPK/mTOR-dependent autophagy, thereby suppressing LTA-induced autophagic dysregulation. These findings provide a theoretical basis for further research into alternative, non-antibiotic strategies for mastitis control.
Neutrophil extracellular traps-related biomarkers in idiopathic pulmonary arterial hypertension: A machine learning-based identification and experimental validation study.
Ma Q, You S
Mol Immunol · 2026 Jul · PMID 42085826 · Publisher ↗
Neutrophil extracellular traps (NETs) are increasingly recognized as critical mediators in vascular inflammation and remodeling, yet their molecular mechanisms in idiopathic pulmonary arterial hypertension (IPAH) pathoge...
Neutrophil extracellular traps (NETs) are increasingly recognized as critical mediators in vascular inflammation and remodeling, yet their molecular mechanisms in idiopathic pulmonary arterial hypertension (IPAH) pathogenesis remain largely unexplored. This study employed integrated bioinformatics approaches and experimental validation to identify NETs-related biomarkers in IPAH. We performed weighted gene co-expression network analysis (WGCNA) on merged transcriptomic datasets (GSE117261 and GSE48149, comprising 40 IPAH and 34 control samples), identifying a blue module significantly correlated with IPAH status. By intersecting module genes with 69 known NETs-related genes, we obtained 19 differentially expressed NETs-related genes (DE-NRGs) enriched in neutrophil degranulation, interleukin-6 regulation, and NETs formation pathways. Three complementary machine learning algorithms converged on five key biomarkers: CSF3R, MGAM, ITGAM, TLR8 (downregulated), and SELP (upregulated). These biomarkers demonstrated strong diagnostic performance in an independent validation cohort, with an area under the curve greater than 0.8. Immune infiltration analysis revealed significantly decreased neutrophils, macrophages, and myeloid-derived suppressor cells in IPAH patients. Single-cell RNA sequencing validated cell-type-specific expression patterns, with CSF3R predominantly in neutrophils, ITGAM/TLR8 in macrophages, and SELP in endothelial cells. Critically, monocrotaline-induced rat pulmonary arterial hypertension model confirmed significant downregulation of MGAM, CSF3R and ITGAM at protein levels. Our findings establish a NETs-related molecular signature for IPAH diagnosis and reveal impaired neutrophil function as a key pathogenic mechanism in IPAH, providing novel molecular targets for therapeutic intervention and risk stratification.
Sinigrin inhibits PD-L1 expression via suppressing the JAK-STAT signaling pathway to modulate the tumor immune microenvironment in lung cancer.
Zhu N, Yu Z
Mol Immunol · 2026 Jul · PMID 42070508 · Publisher ↗
Lung cancer is one of the most common malignant tumors worldwide. During the development and progression of lung cancer, the increase in PD-L1 expression inhibits T cell activity, leading to an immunosuppressive tumor mi...
Lung cancer is one of the most common malignant tumors worldwide. During the development and progression of lung cancer, the increase in PD-L1 expression inhibits T cell activity, leading to an immunosuppressive tumor microenvironment. Sinigrin (Sin) is a natural aliphatic glucoside with various pharmacological effects such as anti-cancer and immunomodulation. However, its role in lung cancer and the underlying mechanism remain unclear. This study aims to explore the therapeutic potential and molecular mechanism of sinigrin in improving the immune microenvironment of lung cancer. Experiments conducted in vitro demonstrated that sinigrin can effectively inhibit the viability, proliferation and migration of cancer cells, promote their apoptosis, and significantly reduce the expression level of PD-L1. Moreover, the effect of sinigrin on cancer cells is dose-dependent. The results of in vivo experiments indicated that sinigrin can effectively inhibit tumor growth and proliferation, promote tumor cell apoptosis, suppress the expression of PD-L1, enhance T-cell activation, and improve the tumor immune microenvironment. Network pharmacology and in vitro experimental analyses revealed that sinigrin exerts its therapeutic effect by inhibiting the expression of PD-L1 through the JAK/STAT signaling pathway. Sinigrin inhibits the expression of PD-L1 by suppressing the JAK-STAT signaling pathway, thereby improving the immune microenvironment of lung cancer and providing an effective therapeutic strategy for blocking the progression of lung cancer.
Glutathione depletion activates cGAS-STING signaling via oxidative stress in preeclampsia.
Hu S, Liu W, Dong Y … +17 more , Wu S, Zhao S, Zheng Y, Li C, Si D, Chen J, Su S, Han J, Cao Y, Lu Y, Meng L, Xu Z, Song L, Wang Y, Lu T, Zhai Y, Cao Z
Mol Immunol · 2026 Jul · PMID 42068604 · Publisher ↗
Oxidative stress can cause double-strand breaks in DNA in patients with preeclampsia (PE), but whether the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is involved in PE remains unclear....
Oxidative stress can cause double-strand breaks in DNA in patients with preeclampsia (PE), but whether the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is involved in PE remains unclear. Here, we show that glutathione (GSH) metabolism is disrupted in placentas from PE patients, leading to increased oxidative stress and activation of the cGAS-STING pathway. Using metabolomics and and CRISPR-Cas9 generated cGAS/STING knockout human trophoblast cells, we found that GSH depletion elevate reactive oxygen species (ROS) levels in HTR-8/SVneo cells, leading to cellular DNA damage and the release of double-stranded DNA (dsDNA) into the cytosol. This activates the cGAS-STING signalling, promoting NF-κB-mediated inflammatory and type I interferon responses. This mechanism highlights the critical role of ROS-mediated DNA damage and cGAS-STING-dependent inflammation in PE development, suggesting potential therapeutic targets for its intervention.
Siglec-15 promotes M2 polarization of Kupffer cells via DAP12/IRAK-M axis to alleviate acute rejection in liver transplantation.
Luo J, Tu L, Gong J … +2 more , Mei Z, Cheng M
Mol Immunol · 2026 Jun · PMID 42066581 · Publisher ↗
BACKGROUND: Acute rejection (AR) remains a significant issue affecting the efficacy of liver transplantation, and the Kupffer cell (KC) phenotype is crucial for AR. Recent studies have indicated that Siglec-15 can regula...
BACKGROUND: Acute rejection (AR) remains a significant issue affecting the efficacy of liver transplantation, and the Kupffer cell (KC) phenotype is crucial for AR. Recent studies have indicated that Siglec-15 can regulate macrophage polarization. However, the role of Siglec-15 in liver transplantation remains unclear. METHODS: Immune tolerance (BN-BN) and immune rejection (Lewis-BN) models were developed in rats to assess the expression of Siglec-15 in KCs. Clinical specimens were also collected for further validation. Then, in vitro experiments were conducted to explore the function and specific mechanisms of Siglec-15 in regulating KC polarization. Finally, Siglec-15 was overexpressed in rats to evaluate its impact on AR. RESULTS: Compared to the immune tolerance group, the expression of Siglec-15 in KCs was lower in the immune rejection group. Similarly, Siglec-15 levels were significantly decreased in patients with AR, and Siglec-15 expression levels were significantly negatively correlated with AR severity. KCs were isolated from the liver tissue of healthy BN rats and treated with lipopolysaccharide, and overexpressing Siglec-15 promoted M2 polarization of KCs. Mechanistically, the GENEMANIA website predicted that the DNAX-activation protein 12 (DAP12)/interleukin-1 receptor-associated kinase-M (IRAK-M) pathway serves as a potential downstream target of Siglec-15. Molecular docking and in vitro experiments confirmed this result. Further silencing either DAP12 or IRAK-M via siRNA abolished the promoting effect of Siglec-15 on the M2 polarization of KCs. Furthermore, overexpressing Siglec-15 reduced AR and improved survival rates in rats. CONCLUSIONS: Siglec-15 induces M2 polarization of KCs through the DAP12/IRAK-M axis, thereby alleviating AR during liver transplantation. Siglec-15 is a potential effective target for therapeutic intervention in AR.
NAT10 promotes lung cancer progression by enhancing glutamine metabolism through increasing ac4C modification on NIT2.
Yang D, Zhu Y, Liu Y … +1 more , Dai Z
Mol Immunol · 2026 Jun · PMID 42030693 · Publisher ↗
Glutamine metabolism plays a critical role in lung cancer progression due to its substantial contribution to energy supply. NAT10 is currently the only known ac4C transferase and regulates gene expression and mRNA stabil...
Glutamine metabolism plays a critical role in lung cancer progression due to its substantial contribution to energy supply. NAT10 is currently the only known ac4C transferase and regulates gene expression and mRNA stability through ac4C modification, thereby influencing tumor progression. This study aimed to investigate the mechanisms by which NAT10 mediates glutamine metabolism in lung cancer. The UALCAN database was used to perform pan-cancer analysis and assess NAT10 expression in lung cancer. Cell viability, proliferation, and migration were evaluated to characterize malignant behaviors in lung cancer cells. Glutamine metabolism was assessed by measuring glutamine consumption, as well as α-ketoglutarate (α-KG) and ATP production. NAT10-associated genes were identified from the GSE3141 dataset and subjected to pathway enrichment analysis. The underlying mechanism was explored using methylated RNA immunoprecipitation and dual-luciferase reporter assays. The role of NAT10 in lung cancer progression in vivo was assessed using a xenograft model. Results showed that NAT10 was upregulated in lung cancer cells and promoted cell viability, proliferation, migration, and glutamine metabolism in A549 and H460 cells, whereas NAT10 inhibition reversed these effects. Mechanistically, NAT10 enhanced ac4C modification of NIT2 and increased NIT2 mRNA stability. Overexpression of NIT2 restored cell viability, proliferation, migration, and glutamine metabolism that were suppressed by NAT10 knockdown in A549 and H460 cells. Furthermore, inhibition of NAT10 reduced tumor growth and glutamine metabolism in nude mice. Collectively, our findings demonstrate that NAT10 promotes glutamine metabolism in lung cancer by enhancing ac4C modification of NIT2, providing new insights into the mechanisms underlying lung cancer progression.
Wnt7a mediates the Wnt/β-catenin signaling pathway to influence ferroptosis in T lymphocytes of HIV-infected individuals.
Tao Z, Gao J, Huang H … +9 more , Xu T, Zhang T, Liang J, Bao L, Liao S, Mo L, Chi J, Li L, Xie L
Mol Immunol · 2026 Jun · PMID 42025402 · Publisher ↗
Human Immunodeficiency Virus (HIV) infection is characterized by the depletion of human CD4 + T cells, in which ferroptosis has been identified as a contributing mechanism. Dysregulation of the canonical Wnt/β-catenin si...
Human Immunodeficiency Virus (HIV) infection is characterized by the depletion of human CD4 + T cells, in which ferroptosis has been identified as a contributing mechanism. Dysregulation of the canonical Wnt/β-catenin signaling pathway is strongly associated with HIV infection. Our findings demonstrate that Wnt7a activates this pathway. Subsequently, β-catenin translocates to the nucleus, where it interacts with the transcription factor 4 (TCF4) to regulate ferroptosis in T lymphocytes from HIV-infected individuals. Analysis of peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals revealed significantly decreased expression levels of Wnt7a, along with key Wnt/β-catenin pathway components (β-catenin, TCF4) and the ferroptosis regulator GPX4, compared to healthy controls. Concurrently, PBMCs from HIV-infected individuals exhibited elevated levels of ferroptosis. We established an in vitro HIV-infected T lymphocyte model by expanding patient-derived PBMCs using a CD3/CD28/CD2 T cell activator and IL-2. Lentiviral transduction was used to stably overexpress Wnt7a in this model. Wnt7a overexpression successfully activated the Wnt/β-catenin pathway and significantly reduced ferroptosis levels. Furthermore, pharmacological manipulation of ferroptosis modulated Wnt7a expression: treatment with the ferroptosis inhibitor Liproxstatin-1 and Ferrostatin-1 increased Wnt7a expression, while exposure to the ferroptosis inducer RSL-3 decreased it. Flow cytometry analysis confirmed that overexpressing Wnt7a significantly increased the number of CD4 + T cells compared to the control. In summary, Wnt7a activates the Wnt/β-catenin signaling pathway to reduce ferroptosis in T lymphocytes from HIV-infected individuals, likely by targeting GPX4, suggesting a potential new strategy for treating HIV infection by restoring the T lymphocyte population.
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.
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.
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