Cellular & Molecular Immunology[JOURNAL]
Sun
200 papers
Monochromatic green light-mediated melatonin promotes cecal barrier function in broilers.
Quan T, Li R, Chen Y … +1 more , Gao T
Mol Immunol · 2025 Nov · PMID 40974884 · Publisher ↗
Light plays a crucial role as an environmental factor, greatly affecting chick behavior, production performance and health. Melatonin, an essential marker of photoelectric signaling, plays a role in regulating various ph...
Light plays a crucial role as an environmental factor, greatly affecting chick behavior, production performance and health. Melatonin, an essential marker of photoelectric signaling, plays a role in regulating various physiological functions in broilers, such as gut health. However, whether monochromatic light can mediate melatonin secretion to regulate intestinal function and its regulatory mechanism are not known. In the present study, we showed that monochromatic green light significantly enhanced the mucosal barrier function of the broiler cecum, including the up-regulation of goblet cells and their secreted MUC2 content, tight junction protein expression and enterocyte proliferative viability. However, when the pineal gland was removed, accompanied by a decrease in melatonin content, the green light advantage disappeared and the intestinal mucosal barrier function was severely impaired. Mechanistically, we found that monochromatic green light promotes melatonin secretion, which enters the intestine to bind Mel1a receptors located on macrophage membranes in cecum, inhibits its downstream TLR4/ERK/JNK/NF-κB signaling pathway, promotes M2-type macrophage polarization, reduces intestinal inflammation levels while up-regulating intestinal antioxidant levels, and ultimately strengthens the cecum mucosal barrier function. Our findings provide new theoretical support for the future use of melatonin during intestinal development, as well as theoretical guidance for the proper application of artificial lighting in the modern chicken industry to improve chicken's intestinal health.
Profiling of SFTS virus and host protein interactions by affinity purification-mass spectrometry.
Hou W, Lu J, Pan H … +3 more , Wang T, Liu H, Chen R
Mol Immunol · 2025 Nov · PMID 40929771 · Publisher ↗
Severe Fever with Thrombocytopenia Syndrome (SFTS), caused by the novel phlebovirus SFTSV (SFTS bunyavirus), was first identified in 2009 across several Chinese provinces, with a case fatality rate reaching 30 %. Given i...
Severe Fever with Thrombocytopenia Syndrome (SFTS), caused by the novel phlebovirus SFTSV (SFTS bunyavirus), was first identified in 2009 across several Chinese provinces, with a case fatality rate reaching 30 %. Given its compact genome, SFTSV critically depends on host cellular machinery for replication and pathogenesis. In this study, we employed a systematic strategy combining co-immunoprecipitation of viral-host complexes with formaldehyde crosslinking and affinity purification-mass spectrometry (AP-MS) to comprehensively map SFTSV-host interactions. We systematically analyzed protein complexes associated with all five viral structural/non-structural proteins (NP, NSs, Gc, Gn, and L), identifying 432 host proteins as potential viral interactors. Subsequent bioinformatic analysis included Gene Ontology categorization and functional domain/pathway enrichment analysis via KEGG, with interaction networks visualized through Cytoscape. Importantly, we experimentally validated key interactions between NSs and host proteins VDAC1, Vimentin, and HSP90AB1, demonstrating robust consistency with our mass spectrometry findings.
Characterization of the heterogeneity in oxidative stress and transcriptional programs within the in vivo microenvironment of ulcerative colitis.
Zhuang Y, Ye R, Chen J … +5 more , Chen G, Chen L, Zhu Y, Ye S, Liu Y
Mol Immunol · 2025 Nov · PMID 40929770 · Publisher ↗
OBJECTIVE: Oxidative stress exerts an essential role in the pathogenesis of ulcerative colitis (UC). This study aims to unveil the heterogeneity in oxidative stress among immune cell subpopulations in UC. METHODS: Human...
OBJECTIVE: Oxidative stress exerts an essential role in the pathogenesis of ulcerative colitis (UC). This study aims to unveil the heterogeneity in oxidative stress among immune cell subpopulations in UC. METHODS: Human colon epithelial cells were exposed to 100 ng/mL LPS to stimulate UC, which were administrated with antioxidants 500 mM butylated hydroxyanisole or 20 μM N-acetylcysteine. A single-cell atlas was constructed across UC, and heterogeneous cell subpopulations were evaluated at single-cell and bulk levels. RESULTS: Activation of oxidative stress and inflammatory response, enhanced migration capacity, and impaired tight junction were observed in LPS-induced UC cell models, which were ameliorated by antioxidants. Five cell types: plasma cells, T cells, myeloid cells, and B cells were clustered across UC and control gut biopsies, which were tightly interacted. Myeloid cells were sub-clustered into conventional dendritic cells, M1 macrophages, IL23R myeloid cells, mast cells, and follicular dendritic cells; T cells were sub-clustered into Th17, CD4 naïve T cells, CD8 cytotoxic T cells, CD4 exhausted T cells, CD8 memory T cells, Tregs, and Th1. The heterogeneous myeloid and T cells was confirmed at the single-cell and bulk levels. The activity of oxidative stress was heterogeneous among diverse myeloid cell or T cell subpopulations, with the strongest activity in M1 macrophages and CD4 exhausted T cells, respectively. It was also found the specific transcriptional programs of M1 macrophages and CD8 cytotoxic T cells. CONCLUSION: Overall, our findings unveil the heterogeneity in oxidative stress and transcriptional programs among diverse myeloid and T cell subpopulations in UC.
SNHG16-loaded extracellular vesicles from hypoxic NSCLC cells drive M2 macrophage polarization to enhance cancer aggressiveness.
Hou Y, Li X, Zeng L … +1 more , Zhang Y
Mol Immunol · 2025 Nov · PMID 40925169 · Publisher ↗
Hypoxia plays a critical role in regulating the progression of non-small cell lung cancer (NSCLC) by modulating the tumor immune microenvironment (TIME). Tumor-associated macrophages (TAMs), important components of TIME,...
Hypoxia plays a critical role in regulating the progression of non-small cell lung cancer (NSCLC) by modulating the tumor immune microenvironment (TIME). Tumor-associated macrophages (TAMs), important components of TIME, can be regulated by hypoxic conditions. Unfortunately, the molecular mechanisms by which hypoxia regulates TAMs in TIME to affect NSCLC progression has not been fully delineated. The present study evidenced that hypoxia-stimulated NSCLC cells secreted extracellular vesicles (EVs) were featured with highly expressed small nucleolar RNA host gene 16 (SNHG16), and SNHG16-containing EVs (SNHG16-EVs) synergistically promoted cell proliferation, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) properties in NSCLC cells, and induced M2-polarization of macrophages in THP-1 cells through delivering SNHG16. Notably, M2-polarized macrophages were capable of enhancing cancer aggressiveness in NSCLC cells through secreting tumor-initiating cytokines, including interleukin-10 (IL-10), transforming growth factor β (TGF-β), and vascular endothelial-derived growth factor (VEGF). Mechanistically, it was found that SNHG16 sponged miR-132-3p to positively regulate its downstream target, kinesin family member 5 A (KIF5A), via a competing endogenous RNA (ceRNA) mechanism-dependent manner. Rescue experiments confirmed that SNHG16-EVs induced NSCLC progression and M2 polarization of THP-1 cells were all reversed by overexpressing miR-132-3p and silencing KIF5A. Collectively, hypoxia-stimulated NSCLC cells transferred SNHG16-containing EVs to promote cancer aggressiveness and M2-polarized macrophages in NSCLC through modulating the downstream miR-132-3p/KIF5A axis, and this study verified that targeting SNHG16-EVs may be a novel strategy to hamper NSCLC progression via modulating TME.
Drice negatively regulates cellular and humoral immunity of Drosophila melanogaster.
Jaiswal P, Tapadia MG
Mol Immunol · 2025 Nov · PMID 40914987 · Publisher ↗
The innate immune response is a double-edged sword in insects, comprising the humoral and cellular mechanisms to fight and eliminate pathogens. The humoral response is achieved by the production of antimicrobial peptides...
The innate immune response is a double-edged sword in insects, comprising the humoral and cellular mechanisms to fight and eliminate pathogens. The humoral response is achieved by the production of antimicrobial peptides, which are secreted in the hemolymph. The cellular responses are mediated by phagocytosis, encapsulation and melanization. Though the fat bodies are the primary immune tissues in Drosophila, secreting AMPs, the Malpighian tubules are also autonomous immune organs that constitutively secrete AMPs at basal levels, which increases after infection. Here we provide evidence to show that the caspase 3 homolog in Drosophila, Drice, negatively regulates both, cellular as well as humoral immunity. Depletion of Drice leads to the increased expression of transcription factor Relish, which enhances the expression of certain AMPs regulated by the IMD pathway. In the absence of Drice, both the Ecdysone receptor- B1 and Broad-core (Br-C) are also upregulated which are upstream regulators of the IMD pathway. The increase in crystal cells clearly indicates Drice to be a negative regulator of this form of cellular immunity. Collectively our findings suggest the role of Drice in the immune regulation of Drosophila melanogaster, and these results will add to the growing understanding of diverse roles of caspases in immune regulation.
MAP30 inhibits proliferation and metastasis of bladder cancer by increasing EGR1 expression and promoting the transcriptional activation of DUSP1.
Wang K, Gu Q, Xue C … +3 more , Shi J, Wang K, He X
Mol Immunol · 2025 Nov · PMID 40914986 · Publisher ↗
The confirmed tumor-inhibitory effects of the 30 kDa Momordica anti-human immunodeficiency virus protein (MAP30) have yet to be complemented by an exploration into its mechanism of action on tumor development and metasta...
The confirmed tumor-inhibitory effects of the 30 kDa Momordica anti-human immunodeficiency virus protein (MAP30) have yet to be complemented by an exploration into its mechanism of action on tumor development and metastasis. For this purpose, we delved into the intrinsic mechanism of MAP30 in bladder cancer (BC). Here, we demonstrated that MAP30 markedly suppressed the proliferation, migration, invasion, and angiogenic capabilities of human BC cells in vitro, and the tumor metastatic potential in vivo. Furthermore, our findings showed that MAP30 suppressed the functional activities of BC cells by upregulating the expression levels of early growth response 1 (EGR1). Additionally, our investigation confirmed that EGR1 and dual specificity phosphatase 1 (DUSP1) were down-expressed in BC and had been identified as closely linked to the advancement of BC. DUSP1 was transcriptionally induced by EGR1, and the expression of EGR1 was found to be positively linked with DUSP1 in human BC tissues. The knockdown of EGR1 was found to boost cell invasion, migration, proliferation, and angiogenesis via the MAPK signaling pathway, however, the overexpression of DUSP1 inhibited EGR1 knockdown-induced promotion of these functional activities in BC cells. Furthermore, MAP30 inhibited the invasion, migration, proliferation, and angiogenesis of BC cells by regulating the EGR1-DUSP1 axis. Our study yielded an exhaustive insight into the suppressive actions of MAP30 on BC progression.
Study on the adjuvant activity and mechanism of action of a novel Monophosphoryl Lipid A.
Zhao L, Shi P, Zhang Y … +6 more , Zhang M, Han N, Liu Z, Li S, Yin J, Zhai J
Mol Immunol · 2025 Nov · PMID 40907461 · Publisher ↗
In order to develop a novel vaccine adjuvant that is highly efficient, cost-effective, and suitable for widespread application, this study employed synthetic biology techniques to produce a new type of Escherichia coli m...
In order to develop a novel vaccine adjuvant that is highly efficient, cost-effective, and suitable for widespread application, this study employed synthetic biology techniques to produce a new type of Escherichia coli monophosphate lipid A (N-MPL). Specifically, the phosphate group attached to the C-1 position was removed, and a hydroxyl group was introduced into the 3'-secondary fatty acid chain of the original lipid A structure. This modification aimed to reduce toxicity while enhancing water solubility. Two formulations of N-MPL were prepared and their immunological and adjuvant activities were evaluated. Results demonstrated that both formulations could promote the proliferation of immune cells and the maturation of bone marrow-derived dendritic cells (BMDCs). In an adjuvant immunization experiment using H1N1 vaccine in ICR mice, N-MPL exhibited superior adjuvant effects compared to aluminum adjuvants and commercially available Monophosphoryl Lipid A (Synthetic) (PHAD™). Through comprehensive analysis of splenic lymphocytes, antibodies, cytokines, and immune factors in immunized mice, it was discovered for the first time that different formulations of N-MPL adjuvants could regulate cellular and humoral immunity, albeit with distinct foci of induced immune responses. The oil-in-water formulation of N-MPL primarily induced cellular immune responses in mice, whereas the aqueous solution formulation predominantly elicited humoral immune responses. Mechanistic studies revealed that N-MPL regulates the Th1/Th2 response via the TLR4-MyD88-NF-κB signaling pathway. Overall, the novel N-MPL adjuvant exhibits high efficiency and low cost, demonstrating significant potential for vaccine adjuvant development.
SMAD7-mediated ferroptosis in macrophages drives osteoporosis progression: A multi-omics study.
Li Q, Tu Y, Diao H … +2 more , Zheng L, Chen W
Mol Immunol · 2025 Nov · PMID 40897147 · Publisher ↗
Osteoporosis (OP) is characterized by imbalanced bone homeostasis, which is difficult to precisely regulate with current therapeutic strategies. Macrophages play a significant role in bone remodeling due to their complex...
Osteoporosis (OP) is characterized by imbalanced bone homeostasis, which is difficult to precisely regulate with current therapeutic strategies. Macrophages play a significant role in bone remodeling due to their complex interactions with osteoclasts and osteoblasts, suggesting that targeting macrophage-related pathways could offer novel therapeutic opportunities. To explore this, we combined bulk RNA-seq and scRNA-seq data to identify macrophage-related genes. Using bioinformatic tools, including CIBERSORT, WGCNA, and machine learning algorithms, we identified 1705 macrophage marker genes and 839 macrophage module genes. Enrichment analysis revealed that the intersection genes were significantly enriched in the ferroptosis signaling pathway, highlighting its critical role in macrophages. Further validation through protein-protein interaction networks and cellular communication analysis confirmed the importance of ferroptosis in macrophage. Using artificial neural network, we identified 4 macrophage hub genes, with SMAD7 showing the greatest weight. Experimental validation using RAW264.7 cells, immunohistochemistry, and micro-CT analysis further demonstrated the association of ferroptosis-related indicators (Fe and lipid peroxidation) with bone damage in osteoporosis patients. And we found SMAD7 showing the strongest correlation with trabecular microstructural deterioration. Notably, our findings also confirmed that the SMAD7 inhibitor mongersen effectively attenuated macrophage ferroptosis, suggesting its potential to improve bone microstructural integrity. Our study demonstrates that SMAD7-mediated macrophage ferroptosis is a critical mechanism in osteoporosis pathogenesis, highlighting SMAD7 as a promising therapeutic target.
CCL5: An emerging key target and progress in the targeted therapy of hepatocellular carcinoma.
Liu X, Liang J, Zhao L … +12 more , Li W, Wang L, Wang X, Liu Y, Zhou M, Li X, Jia Z, Song M, Zhang L, Yang Y, Cai J, Zhang B
Mol Immunol · 2025 Nov · PMID 40885001 · Publisher ↗
Hepatocellular carcinoma (HCC) is a highly prevalent and lethal malignancy, presenting significant challenges in clinical diagnosis and treatment. The chemokine C-C motif ligand 5 (CCL5) plays a pivotal role in HCC patho...
Hepatocellular carcinoma (HCC) is a highly prevalent and lethal malignancy, presenting significant challenges in clinical diagnosis and treatment. The chemokine C-C motif ligand 5 (CCL5) plays a pivotal role in HCC pathogenesis. While traditionally viewed primarily as a mediator of immune cell chemotaxis and migration, recent evidence demonstrates that CCL5 directly influences tumor cells, regulating malignant behaviors such as proliferation and invasion. Furthermore, CCL5 recruits diverse immune cells, including immunosuppressive populations, to the tumor microenvironment (TME), remodeling the TME and exerting context-dependent effects that can either promote immune evasion or enhance anti-tumor immunity. This article reviews advances in understanding the mechanisms of CCL5 in HCC and discusses the translational potential of targeting CCL5 for HCC therapy.
JAK/STAT pathway in myocardial infarction: Crossroads of immune signaling and cardiac remodeling.
Yang Q, Ji H, Modarresi Chahardehi A
Mol Immunol · 2025 Oct · PMID 40882407 · Publisher ↗
Myocardial infarction (MI) initiates a robust immune-inflammatory response in which dysregulated cytokine signaling exacerbates tissue damage and adverse cardiac remodeling. The Janus kinase/signal transducer and activat...
Myocardial infarction (MI) initiates a robust immune-inflammatory response in which dysregulated cytokine signaling exacerbates tissue damage and adverse cardiac remodeling. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway serves as a key mediator of cytokine signaling and immune cell activation, playing a dual role in post-MI outcomes. On one hand, JAK/STAT activation supports cardioprotective mechanisms such as angiogenesis and anti-apoptotic signaling; on the other hand, its excessive or prolonged activation contributes to maladaptive inflammation, fibrosis, and heart failure. This review examines how pro-inflammatory cytokines (e.g., IL-6, TNF-α) and immune cells (e.g., macrophages, neutrophils) activate the JAK/STAT pathway in ischemic myocardium. We discuss the pathway's crosstalk with inflammatory signaling networks, including NF-κB, MAPK, and PI3K/Akt, and evaluate the potential of repurposing JAK inhibitors (e.g., ruxolitinib) to modulate immune responses after MI, drawing insights from clinical trials in autoimmune diseases. Unresolved challenges such as cell-specific effects of JAK/STAT modulation and the need for biomarker-driven therapies are also highlighted. By synthesizing current preclinical and clinical evidence, this review proposes a framework for immune-targeted strategies aimed to improving cardiac outcomes following MI.
Curcumin modulates tracheal epithelial cell autophagy in asthma by inhibiting the NF-κB pathway via SCGB3A2.
Wang T, Huang W, Long L … +4 more , Fu P, Wang Q, Long F, Liu S
Mol Immunol · 2025 Oct · PMID 40865253 · Publisher ↗
BACKGROUND AND OBJECTIVE: Asthma, a chronic inflammatory airway disease, presents a significant global health burden. This study aimed to elucidate the mechanism by which curcumin modulates tracheal epithelial cell autop...
BACKGROUND AND OBJECTIVE: Asthma, a chronic inflammatory airway disease, presents a significant global health burden. This study aimed to elucidate the mechanism by which curcumin modulates tracheal epithelial cell autophagy in asthma, with a specific focus on its interplay with SCGB3A2 and the NF-κB pathway. METHODS: An in vitro asthma model was mimicked using 16HBE cells treated with TDI. Concurrently, a TDI-induced asthma model was built in Balb/c mice for in vivo investigations. Cells or mice were subjected to curcumin treatment, and SCGB3A2 was knockdown or overexpressed, to explore the function of SCGB3A2. TNF-α and TPCA-1 were also utilized to mediate activation of NF-κB in vitro. Western blot, qPCR, ELISA, immunofluorescence, and transmission electron microscopy were employed to assess SCGB3A2 expression, NF-κB pathway activation, autophagy, key inflammatory cytokines, and airway remodeling indicators. RESULTS: TDI stimulation reduced SCGB3A2 expression in 16HBE cells. SCGB3A2 overexpression mitigated TDI-induced inflammation and airway remodeling by inhibiting the NF-κB pathway and enhancing autophagy. Subsequent NF-κB activation partially abrogated these SCGB3A2-mediated protective effects on inflammation, airway remodeling, and autophagy. Curcumin treatment upregulated SCGB3A2, inhibited NF-κB activation, and promoted autophagy; these protective effects were substantially diminished upon SCGB3A2 knockdown. In vivo, curcumin administration ameliorated asthma features, evidenced by reduced airway inflammation, suppressed NF-κB, and enhanced autophagy in tracheal epithelial tissues. CONCLUSIONS: This study reveals that curcumin protects against asthma by modulating the SCGB3A2-NF-κB-autophagy axis. These findings highlight this axis as a novel therapeutic target for asthma.
The circERBB3/chi-miR-181b-5p/TNFSF11 axis regulates proliferation, migration, and apoptosis in cashmere goat embryonic fibroblasts.
Rong Y, Pan J, Niu S … +10 more , Ao X, Wang Y, Shang F, Lv Q, Wang Z, Wang R, Su R, Zhao Y, Wang Y, Zhang Y
Mol Immunol · 2025 Oct · PMID 40865251 · Publisher ↗
BACKGROUND: Inner Mongolia cashmere goat is an excellent local variety of both cashmere and meat. Its cashmere is delicate and soft and has high economic value. The morphogenesis and development of hair follicles directl...
BACKGROUND: Inner Mongolia cashmere goat is an excellent local variety of both cashmere and meat. Its cashmere is delicate and soft and has high economic value. The morphogenesis and development of hair follicles directly affect the wool yield and quality of cashmere goats. Circular RNAs are endogenous, non-coding RNAs found in eukaryotic genomes that are involved in a variety of physiological and pathological processes. However, the potential function of circRNA in the development of embryonic skin hair follicles in cashmere goats remains unknown. RESULTS: In this study, we identified a novel circular RNA, circERBB3, isolated fibroblasts from cashmere goat embryonic skin tissue, and investigated its role in fibroblast proliferation, apoptosis, and migration. The interaction between circERBB3, chi-miR-181b-5p, and TNFSF11 was detected by bioinformatics, real-time quantitative PCR, and the dual luciferase reporter gene system. Mechanistically, we demonstrated the functional significance of circERBB3 by interfering with circERBB3 in fibroblasts. At the molecular and cellular levels, co-transfection tests confirmed that circERBB3 negatively regulated fibroblast proliferation, apoptosis, and migration in a chi-miR-181b-5p-dependent manner. Chi-miR-181b-5p can regulate the proliferation, apoptosis, and migration of fibroblasts by targeting TNFSF11. CONCLUSIONS: As a competitive endogenous RNA, circERBB3 binds to chi-miR-181b-5p and alleviates the inhibition of its target gene, TNFSF11, to regulate the proliferation, apoptosis, and migration of embryonic fibroblasts in cashmere goats. A new regulatory pathway regulating the development of hair follicles was revealed.
The protective role of Astragaloside IV in adriamycin-induced renal injury: A focus on macrophage polarization and PPARγ activation.
Li A, Wang M, Guo M … +5 more , Liu Y, Li K, Zhang L, Qin X, Liu G
Mol Immunol · 2025 Oct · PMID 40858073 · Publisher ↗
Astragali Radix (AR), a homologous of medicine and food, has been extensively recorded to possess a nephroprotective impact on individuals suffering from chronic kidney disease (CKD). Astragaloside IV (ASIV) is one of th...
Astragali Radix (AR), a homologous of medicine and food, has been extensively recorded to possess a nephroprotective impact on individuals suffering from chronic kidney disease (CKD). Astragaloside IV (ASIV) is one of the prominent bioactive constituents derived from AR. This study aimed to investigate how ASIV promotes M2 polarization of macrophages and whether this contributes to the protection of podocytes from injury, using a combination of lipidomics and molecular biology techniques.The effect of ASIV on adriamycin (ADR)-induced renal injury in rats was evaluated in vivo, with a particular emphasis on elucidating the potential involvement of macrophages. The M1 polarization model of RAW264.7 cells induced by ADR was established in vitro. The impact of ASIV on ADR-induced macrophage polarization was comprehensively assessed by measuring the expression levels of M1 and M2 macrophage marker proteins, along with their associated mRNA profiles. Flow cytometry was employed to analyze surface marker expression, while Western blot (WB) was used to quantify protein levels, and real-time quantitative PCR (qPCR) allowed for the measurement of gene expression. Notably, we found that the macrophage supernatant intervened by ASIV was found to have a protective effect against podocyte injury, which was evaluated through cell adhesion and apoptosis assays. Innovatively, we explored the mechanism by which ASIV affects macrophage polarization from the perspective of lipid metabolism, using lipidomics methods. During this process, the role of peroxisome proliferator-activated receptor gamma (PPARγ) in macrophage polarization caught our attention. This receptor is closely associated with lipid metabolites, as confirmed by molecular docking. ASIV has been shown to effectively ameliorate kidney injury, with macrophages playing a pivotal role in renal podocyte repair process. The protein and mRNA expressions of ARG-1, CD206 and IL-10, M2 macrophage markers, was increased by ASIV and M2 macrophages polarization was promoted by ASIV (P < 0.05). In addition, it was observed that the supernatant of macrophages intervened by ASIV exerts a protective effect on podocyte injury, which was confirmed through podocyte adhesion assays and cell apoptosis experiments. This study suggests that ASIV enhances the M2 polarization of macrophages, and the supernatant from these polarized macrophages has a protective effect on podocytes. From the perspective of lipid metabolism, the underlying mechanism of this effect may involve the modulation of sphingolipids, arachidonic acid, glycerophospholipids, and other lipid metabolites, which activate the receptor PPARγ, thereby exerting protective effects on podocytes.
Exosomal miR-214-3p reprograms BMSC fate: A novel intercellular mechanism linking vascular insufficiency to impaired bone regeneration in nontraumatic ONFH.
Lin S, Xia J, Ding J … +1 more , Wan J
Mol Immunol · 2025 Oct · PMID 40848387 · Publisher ↗
BACKGROUND: Nontraumatic osteonecrosis of the femoral head (NONFH) is a debilitating bone disorder of unclear etiology, characterized by impaired bone regeneration and reduced vascularization. However, the influence of N...
BACKGROUND: Nontraumatic osteonecrosis of the femoral head (NONFH) is a debilitating bone disorder of unclear etiology, characterized by impaired bone regeneration and reduced vascularization. However, the influence of NONFH-derived exosomes on bone marrow stromal cell (BMSC) differentiation and angiogenesis remains poorly understood. METHODS: Exosomes were isolated from femoral head tissues of NONFH patients and fracture controls (femoral neck fractures). Their characteristics were confirmed by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot. BMSCs were treated with different exosomes (control exosomes, NONFH exosomes, or NONFH exosomes + miR-214-3p inhibitor), and osteogenic/adipogenic differentiation was assessed by alkaline phosphatase activity, calcium deposition, osteogenic/adipogenic marker expression, and Oil Red O staining. Human umbilical vein endothelial cells (HUVECs) were similarly treated, and angiogenesis was evaluated via tube formation assays. In vivo, exosomes were injected into rats, and femoral changes were analyzed by Western blot, hematoxylin-eosin (HE) staining, and immunohistochemistry. RESULTS: Exosomes from both groups exhibited typical morphology, size, and marker expression. NONFH exosomes suppressed BMSC osteogenesis, enhanced adipogenesis, and impaired HUVEC angiogenesis, with miR-214-3p as a critical mediator. Inhibiting miR-214-3p partially restored osteogenic and angiogenic capacities. In rats, NONFH exosomes reduced osteogenic protein expression, expanded marrow cavities, and disrupted trabecular bone structure, while miR-214-3p inhibition ameliorated these effects. CONCLUSION: NONFH-derived exosomes contribute to disease progression by delivering miR-214-3p, which inhibits BMSC osteogenesis and HUVEC angiogenesis. Targeting this pathway may offer novel therapeutic strategies for NONFH.
Sigmoidin B attenuates sepsis-associated encephalopathy through EZH2-AKT2-mediated regulation of microglial polarization.
Wang Z, Liu Y, Liu Y … +3 more , Li Q, Wang Z, Mu D
Mol Immunol · 2025 Oct · PMID 40834508 · Publisher ↗
PURPOSE: Enhancer of zeste homolog (EZH2) is a potential target in treatment of sepsis. The current study is aimed to screen a novel EZH2 degrader agent based on the Traditional Chinese Medicine Database YaTCM. This may...
PURPOSE: Enhancer of zeste homolog (EZH2) is a potential target in treatment of sepsis. The current study is aimed to screen a novel EZH2 degrader agent based on the Traditional Chinese Medicine Database YaTCM. This may provide an important clue for development of new drugs to treat sepsis-associated encephalopathy (SAE). METHODS: Macrophage-specific EZH2 knockout mice were used to observe the effects of EZH2 on the survival rate, levels of inflammatory cytokines, S100B, CD86, and CD206 in sepsis mice. Sigmoidin B was screened as the novel EZH2 degrader based on the structure of MS177 using large-scale virtual high-throughput screening. Molecular dynamics simulations and MMGBSA analysis were used to assess the stability and binding characteristics of Sigmoidin B. The protective effect of MS177 and the novel EZH2 degrader were verified using in vivo and vitro experiments. RESULTS: Macrophage-specific knockout of EZH2 had been shown to enhance the survival rate in mice with sepsis, reduce levels of CD86 and TNF-α, promote the expression of IL-10 and CD206, and mitigate the extent of brain injury. Sigmoidin B exhibited strong binding affinity to EZH2 and featured a flavonoid core structure along with an olefin side chain. Molecular validation experiments confirmed that Sigmoidin B could ameliorate cognitive dysfunction and modulate microglial polarization via the EZH2-AKT2 pathway. Notably, Sigmoidin B demonstrated superior efficacy compared to MS177 in alleviating inflammation. CONCLUSION: Natural compound Sigmoidin B was successfully screened and confirmed as a novel EZH2 degrader, which was a potential target for the development of new therapeutic for SAE.
NRF1 alleviates cerebral ischemia-reperfusion injury by transcriptionally activating FTO and downregulating m6A-mediated FOXO1 expression.
Zou R, Yu F, Wang M … +1 more , Jia Z
Mol Immunol · 2025 Oct · PMID 40834507 · Publisher ↗
BACKGROUND: Studies show that upregulation of Nuclear respiratory factor 1 (NRF1) inhibits cerebral ischemia-reperfusion injury (CIRI). However, the molecular mechanism of NRF1 in CIRI remains to be largely unrevealed. T...
BACKGROUND: Studies show that upregulation of Nuclear respiratory factor 1 (NRF1) inhibits cerebral ischemia-reperfusion injury (CIRI). However, the molecular mechanism of NRF1 in CIRI remains to be largely unrevealed. Therefore, in this study, we aimed to investigate the potential mechanisms by which NRF1 regulates OGD/R-mediated neuronal apoptosis and its effects on CIRI in rats. METHODS: A middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established to detect the expression of NRF1 in brain tissues of MCAO/R rats. Next, neuronal cells were treated with oxygen-glucose deprivation/reperfusion (OGD/R) and transfected with NRF1 overexpression vectors (pcDNA-NRF1), and cell apoptosis, inflammatory reaction and oxidative stress were evaluated. Furthermore, the enrichment of NRF1 in the promoter of fat mass and obesity-related genes (FTO) was evaluated with ChIP analysis, and the transcriptional activation of FTO by NRF1 was evaluated with luciferase reporter gene analysis. The m6A level of forkhead box O1 (FOXO1) mRNA was evaluated by MeRIP analysis, and the binding of FTO to FOXO1 mRNA was evaluated by RIP analysis. FTO siRNA and FOXO1 overexpression vectors (pcDNA-FOXO1) were transfected into NRF1 overexpressing neuronal cells to perform reversal experiments. Finally, MCAO/R rats were intracranially injected with NRF1 lentiviral vectors (LV-NRF1), and the volume of cerebral infarction, pathological damage and neuronal apoptosis were determined. RESULTS: NRF1 was downregulated in brain tissues of MCAO/R rats and OGD/R-treated neurons. Overexpression of NRF1 inhibited cell apoptosis and reduced inflammatory factor secretion (IL-1β and TNF-α) and oxidative stress (SOD activity was increased and MDA content was decreased) in OGD/R-treated neuronal cells. Mechanistic studies shown that NRF1 promotes FTO transcriptional activation by binding to the FTO promoter, while FTO interference upregulates FOXO1 expression by increasing the m6A level of FOXO1 mRNA. Silencing FTO or overexpression of FOXO1 reversed the inhibitory effect of NRF1 overexpression on OGD/R-induced neuronal damage. In addition, upregulation of NRF1 reduced the volume of cerebral infarction and alleviated neurological impairment and neuronal apoptosis in MCAO/R rats. CONCLUSIONS: This study revealed that NRF1 inhibited neuronal apoptosis and alleviated neurological deficits and neuro-inflammation in MCAO/R rats by promoting FTO-m6A-mediated downregulation of FOXO1, which may provide a potential therapeutic strategy for CIRI.
DAP12 affects the acute inflammatory response caused by UPEC or LPS by regulating macrophage infiltration.
Sun S, Yi R, Wang X … +8 more , Zhang Y, Liu M, Wang L, Niu Z, Jia R, Dong Z, Xiong H, Wang C
Mol Immunol · 2025 Oct · PMID 40834506 · Publisher ↗
Urinary tract infection (UTI) is a prevalent bacterial infection, predominantly caused by uropathogenic Escherichia coli (UPEC). Severe UTIs can lead to kidney damage, which is closely associated with increased infiltrat...
Urinary tract infection (UTI) is a prevalent bacterial infection, predominantly caused by uropathogenic Escherichia coli (UPEC). Severe UTIs can lead to kidney damage, which is closely associated with increased infiltration of M1-type macrophages. DNAX-activating protein of 12 kD (DAP12) is extensively expressed in myeloid cells and natural killer (NK) cells, and it can interact with TREM receptors to mediate various immune responses. Our study revealed that DAP12 deletion significantly mitigated kidney injury induced by UPEC infection, a phenomenon strongly correlated with reduced macrophage infiltration. Further investigation demonstrated that DAP12 directly regulates the polarization of macrophages during UPEC infection. In an endotoxin shock model induced by LPS derived from E. coli, DAP12 deficiency similarly decreased mortality and inhibited LPS-induced macrophage polarization in mice. Collectively, these findings suggest that the TREM1-DAP12 signaling pathway plays a critical role in kidney injury caused by UPEC infection, indicating that this pathway could serve as a novel therapeutic target for treating UPEC-induced kidney damage.
Formononetin ameliorates allergic asthma by inhibiting JUN and suppressing type Ⅱ immune responses mediated by ILC2 cells.
Liu J, Li Y, Liu M … +3 more , Li X, Liu C, Zhu Y
Mol Immunol · 2025 Oct · PMID 40834505 · Publisher ↗
OBJECTIVE: Formononetin (FM), a flavonoid with potent anti-inflammatory effect, was investigated for its therapeutic potential and underlying mechanisms in allergic asthma (AS). METHODS: An ovalbumin (OVA)-induced murine...
OBJECTIVE: Formononetin (FM), a flavonoid with potent anti-inflammatory effect, was investigated for its therapeutic potential and underlying mechanisms in allergic asthma (AS). METHODS: An ovalbumin (OVA)-induced murine model of AS was established and treated with FM. Inflammatory responses, mucus secretion, and the activation and migration of type II innate lymphoid cells (ILC2s) were assessed using histological staining, ELISA, flow cytometry, and molecular analysis. The role of the JUN gene was further explored using the JUN agonist 15(S)-HpETE. In vitro assays were conducted to evaluate FM's effects on ILC2 proliferation and cytokine expression. RESULTS: FM significantly alleviated airway inflammation, reduced mucus hypersecretion, and lowered serum IgE levels. It decreased the abundance and activation of ILC2s in lung tissues and suppressed the expression of related cytokines and transcription factors. Notably, FM inhibited the lung-gut axis migration of ILC2s by reducing iILC2 and nILC2 levels in the small intestine and iILC2 levels in the lung. In vitro, FM suppressed ILC2 proliferation and activation. These effects were reversed by 15(S)-HpETE, suggesting a JUN-dependent mechanism. CONCLUSIONS: FM ameliorates AS by inhibiting type II immune responses and ILC2 migration via targeting JUN. These findings suggest FM as a promising candidate for asthma therapy.
ALKBH5-mediated mA demethylation modification of RAD51 inhibits osteogenic differentiation via promoting DNA damage in osteoporosis.
Qiu M, Liao Z, Wu X … +4 more , He P, Wen X, Xie Y, Qi J
Mol Immunol · 2025 Oct · PMID 40819549 · Publisher ↗
Osteoporosis (OP) is a metabolic disorder characterized by reduced bone mineral density and degeneration of bone tissue microarchitecture. Osteogenic differentiation plays a pivotal role in OP pathogenesis by facilitatin...
Osteoporosis (OP) is a metabolic disorder characterized by reduced bone mineral density and degeneration of bone tissue microarchitecture. Osteogenic differentiation plays a pivotal role in OP pathogenesis by facilitating new bone formation, preserving bone strength and density, and counteracting bone resorption. RNA epigenetic modifications have been increasingly implicated in multiple aspects of bone metabolism. Our previous studies revealed the regulatory role of RAD51 in OP progression. This study aimed to investigate whether RAD51 undergoes RNA methylation modification to participate in OP and to elucidate its underlying mechanisms. MC3T3-E1 cells were induced to undergo osteogenic differentiation and exposed to a simulated microgravity environment to establish an in vitro OP model. An ovariectomized (OVX) murine OP model was also established. RNA methylation level was quantified using dot blot assay. RT-qPCR was employed to analyze mRNA expression of mA methyltransferases and demethylases. Osteogenic differentiation capacity was assessed by Alizarin Red S and alkaline phosphatase (ALP) staining. Protein expressions were evaluated by Western blot. The interaction between RAD51 and AlkB Homolog 5 (ALKBH5)/YTH domain family (YTHDF)1 was validated through RNA immunoprecipitation and dual-luciferase reporter assays. Results demonstrated that ALKBH5-mediated mA demethylation significantly suppressed RAD51 expression in MC3T3-E1 cells. Furthermore, ALKBH5 knockdown enhanced osteoblast differentiation by alleviating DNA damage. Mechanistically, the ALKBH5/YTHDF1 mA regulatory axis modulated RAD51 mRNA stability through mA methylation dynamics. In vivo experiments revealed that ALKBH5 deletion mitigated bone loss and promoted osteoblastogenesis in OVX mice through inhibition of DNA damage pathways. Collectively, these findings indicated that ALKBH5-mediated mA demethylation of RAD51 inhibited osteogenic differentiation by inducing DNA damage in OP, suggesting potential therapeutic targets for osteoporosis treatment.
Expression of immunogenic cell death-related genes is correlated with the immune microenvironment and predicts prognosis in lung adenocarcinoma.
Gao F, Liang Y, Gong W
Mol Immunol · 2025 Oct · PMID 40819548 · Publisher ↗
Immunogenic cell death (ICD) is a type of regulated cell death that is sufficient to prime adaptive immune responses. Mounting evidence has demonstrated that ICD has the potential to modify the tumor immune microenvironm...
Immunogenic cell death (ICD) is a type of regulated cell death that is sufficient to prime adaptive immune responses. Mounting evidence has demonstrated that ICD has the potential to modify the tumor immune microenvironment through the release of numerous damage-associated molecular patterns (DAMPs), which may contribute to the effects of immunotherapy. We aimed to explore the expression profile of ICD-associated biomarkers in lung adenocarcinoma (LUAD) and construct a prognostic signature based on these genes. In this study, we identified two ICD-associated molecular subgroups with significantly different survival rates. Cluster 1 was associated with a favorable prognosis and a high abundance of immune-infiltrating cells and a relatively high immune status. Functional analyses revealed that the differentially expressed genes (DEGs) between the two subgroups were mainly involved in immune response signaling. In addition, a risk score signature established based on 11 ICD-related genes showed notable potential for predicting the prognosis of patients with LUAD. Analysis of immune profiles indicated that the low-risk group had noticeable immune cell infiltration and was more likely to benefit from immunotherapy. In conclusion, we established a new classification system for LUAD based on the ICD signature. This stratification can notably guide clinical practice for assessment of patient prognosis as well as potential immunotherapy for patients with LUAD.
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