NEUROCHEMISTRY INTERNATIONAL
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2025
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IF 4
Ling Zhu,Congyan Liu,Yang Wang,Xuanang Zhu,Lei Wu,Lvan Chen,Jing Zhou,Fan Wang
Background Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD. Method Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N 6 -methyladenosine (m 6 A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF. Results Stimulation with Aβ 1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m 6 A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα. Conclusion Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.
研究领域:
神经生物学
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医学
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PubMed
高影响因子
Human Cell
·
2025
·Vol. 38
·期 3
·1-14
·
IF 3.1
Zhu Xiao-Yu,Li Pi-Song,Qu Hui,Ai Xing,Zhao Zi-Ting,He Jia-Bei
Radiotherapy resistance, is usually caused by enhanced tumor stemness and poses a significant challenge in treating breast cancer (BRCA). In this study, we investigated the molecular regulatory mechanism of radiotherapy sensitivity in BRCA associated with replication factor C4 (RFC4) and insulin-like growth factor 2 mRNA binding protein 2 mRNA Binding Protein 2 (IGF2BP2). RFC4 expression was increased in BRCA cell lines and tissues, and high RFC4 expression in BRCA patients predicted the occurrence of lymphatic metastasis. RFC4-specific short hairpin RNA sequences or RFC4 coding sequences were subsequently cloned and inserted into plasmid vectors to downregulate or upregulate RFC4 expression. Knockdown of RFC4 attenuated stemness, as evidenced by a reduction in sphere formation and the downregulation of CD44 and SOX2. RFC4 silencing inhibited migration and invasion, promoted apoptosis, and improved sensitivity to radiotherapy (4-Gy X-ray). The results were detected by a wound healing assay, a transwell assay, and flow cytometry. The overexpression of RFC4 had the opposite effect on BRCA cells. Like RFC4 expression, IGF2BP2 expression was also increased in the cancer tissues of breast cancer patients. The results of the dual luciferase assay and RIP assay confirmed the binding of IGF2BP2 to the RFC4 mRNA coding sequence. Knockdown of RFC4 eliminated the effects of IGF2BP2 overexpression on increasing cell viability, invasion, the expression of stemness markers and radioresistance, suggesting that the effect of RFC4 on the stemness of BRCA cells was regulated by IGF2BP2. In conclusion, we reported that RFC4, a key regulator of BRCA progression, promoted radioresistance in BRCA and was positively regulated by IGF2BP2.
研究领域:
肿瘤学
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分子生物学
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医学
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PubMed
高影响因子
Molecular Biomedicine
·
2026
·Vol. 7
·期 1
·62
·
IF 13
Ma Hehua,Hong Yuxin,Xu Zhi,Weng Zuyi,Yang Yuanxun,Song Wei,Li Juan
N 6 -methyladenosine (m 6 A) modifications play a vital role in hepatocellular carcinoma (HCC) progression. However, the function of m 6 A reader proteins in HCC remains poorly understood. Here, we elucidate the role and mechanism of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in HCC. In here, we analyzed IGF2BP2 expression in HCC using bioinformatics and clinical samples. The functional role of the IGF2BP2-RELB regulatory axis in HCC progression was assessed through cytological assays and a xenograft HCC mouse model. RNA sequencing, Western blotting, Actinomycin-D assays, and RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP) assays were performed to investigate the regulatory mechanisms of IGF2BP2 on RELB expression. We found high expression of IGF2BP2 in HCC was positively correlated with poor prognosis. Gain- and loss-of-function assays demonstrated that IGF2BP2 was essential for HCC cell proliferation and migration. IGF2BP2 directly bound to RELB mRNA and enhanced its stability via the KH3/4 domain. Upregulated RELB promoted nuclear translocation of the RELB:p52 dimer, leading to activation of the NF-κB signaling pathway. Furthermore, inhibition of IGF2BP2 and RELB suppressed HCC tumor progression both in vitro and in vivo. Our study demonstrates that IGF2BP2 plays a critical role in HCC progression by stabilizing RELB mRNA and activating the NF-κB signaling pathway. The results suggest that IGF2BP2 may be a potential therapeutic strategy for HCC.
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Chinese Herbal Medicines
·
2026
·
IF 11.2
Hui Fang,Fan Yang,Min Shu,Congjian Shi,Qingxu Ha,Junfa Yang,Xiaodi Jia,Yuansong Sun,Zhenhua Ren,Jian Gao
Objective Hepatic fibrosis remains a major global health burden, often progressing to cirrhosis and hepatocellular carcinoma. Despite extensive research, no effective antifibrotic drugs are clinically approved due to the complexity of hepatic stellate cells (HSCs) activation and metabolic remodeling. Enhanced glycolysis is increasingly recognized as a metabolic hallmark sustaining the profibrotic phenotype of HSCs, representing a key but underexplored therapeutic target. This study explored the antifibrotic effect of 6-gingerol, the principal bioactive compound of Zingiber officinale , and revealed its novel mechanism involving metabolic-epitranscriptomic regulation of HSC activation. Methods Liver fibrosis was induced in C57BL/6 mice by carbon tetrachloride (CCl 4 ) and bile duct ligation (BDL), followed by oral 6-gingerol treatment. Complementary in vitro studies were performed in transforming growth factor- β 1 (TGF- β 1)-stimulated Lieming Xu-2 (LX-2 cells, a human hepatic stellate cell line) and primary HSCs from liver fibrosis mice. Integrated transcriptomics, network pharmacology, molecular docking, and cellular thermal shift assays (CETSA) were combined with functional genetic manipulation to identify and verify molecular targets. Results 6-Gingerol alleviated hepatic injury and collagen deposition in both CCl 4 - and BDL-induced models and improved liver function. Mechanistically, 6-gingerol inhibited glycolysis by downregulating hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA), normalizing pyruvate and lactate metabolism, and restoring mitochondrial respiration. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was identified as an important mediator associated with glycolytic enzyme expression and HSCs activation, and its silencing abolished 6-gingerol’s antifibrotic effects. Conclusion Our study demonstrates that 6-gingerol attenuates hepatic fibrosis by targeting IGF2BP2-dependent glycolytic reprogramming, thereby restoring metabolic homeostasis and inhibiting HSCs activation. These findings uncover a novel metabolic-epitranscriptomic mechanism and suggest that 6-gingerol represents a promising therapeutic strategy for chronic liver diseases
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Feng Chen,Minghua Su,Dong Han,Yifan Wang,Menglong Song
Methyltransferase-like 14 (METTL14) is implicated in the regulation of various inflammatory disorders. However, its function and molecular mechanism in severe acute pancreatitis (SAP) remains unrevealed. Here we reported an increase in METTL14 in the pancreas of SAP mice and cerulein-LPS-treated AR42J cells. METTL14 depletion reversed inflammatory response and ferroptosis by reducing the expression of SAT1 (spermidine/spermine N1-acetyltransferase 1) and ACSL4 (acyl-CoA synthetase long chain family member 4) in an m6A-dependent manner. IGF2BP2 (insulin like growth factor 2 mRNA binding protein 2) could recognize m6A-modified SAT1 and ACSL4 mRNA and enhance their stability. Moreover, METTL14 depletion ameliorated pancreatic injury, inflammation, and ferroptosis induced by SAP. METTL14 overexpression aggravated SAP by promoting ferroptosis in vivo. Therefore, these results demonstrated that METTL14-induced ferroptosis promoted the progression of SAP, and targeting METTL14 or ferroptosis could be a potential strategy for the prevention and treatment of SAP.
研究领域:
分子生物学
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炎症性疾病
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胃肠病学
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PubMed
高影响因子
CYTOKINE
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2023
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IF 3.8
Wei Liu,Hui Zeng
Background Ulcerative colitis (UC) is a chronic and uncontrolled inflammatory bowel disease. N 6 -methyladenine (m 6 A) is a reversible mRNA modification method. IGF2BP2 is an RNA-binding protein regulated by m 6 A methylation. However, understanding of m 6 A-related proteins in UC is limited. This study was to analyze the function and related mechanism of IGF2BP2 in UC. Methods The UC models were established by dextran sulfate sodium (DSS) in NCM460 cells and mice. The expression of IGF2BP2 and GPX4 in UC were detected by qPCR and western blot. The effects of IGF2BP2 on inflammation, ferroptosis and colon injury were measured by gain- and loss-of-function experiments. This study conducted a clinical evaluation of mice using the Disease Activity Index score. The molecular mechanism of IGF2BP2 in ferroptosis were analyzed by m 6 A RNA methylation quantification kit, RNA immunoprecipitation-qPCR analysis, and RNA stability assay. Results IGF2BP2 and GPX4 were under-expressed in DSS-treated UC. IGF2BP2 enhanced the stability of GPX4 mRNA modified by m 6 A. IGF2BP2 overexpression repressed the ROS, MDA, and iron levels but enhanced the GSH and GPX4 levels in DSS-triggered NCM460 cells, which were partially reversed by GPX4 silencing. In UC mice, IGF2BP2 high-expression ameliorated symptoms, Disease Activity Index score, pathological changes, inflammatory reaction, and ferroptosis, which were also partly neutralized by GPX4 inhibition. Conclusions IGF2BP2 augmented the GPX4 expression by the m 6 A modification to weaken UC progression via suppressing ferroptosis.
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Cancer Cell International
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2026
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IF 7
Siyi Liu,Lin Liang,Zihua Zhou,Chenyu Zhang,Shan Liao,Qian He,Yan Lei,Juan Xu,Gengqiu Luo,Yanling Li,Yanhong Zhou
As a cell surface glycoprotein, CD90 plays a significant role in the initiation and progression of malignancies such as gastric cancer (GC) by influencing tumor cell proliferation, migration, and angiogenesis. However, its specific role in immune evasion in GC and its potential therapeutic value have not been fully explored. In this study, we report that CD90 is highly expressed in GC tissues and is positively correlated with macrophage immune infiltration. Furthermore, we demonstrate that CD90 can mediate immune evasion in GC by affecting the phagocytic function of tumor-associated macrophages (TAMs). Mechanistically, CD90 functions as a scaffold protein, inhibiting the interaction between IGF2BP2 and TRIM21. This inhibition stabilizes the expression of the m6A methylation reader protein IGF2BP2. Subsequently, IGF2BP2 enhances the mRNA stability of the immune checkpoint molecule CD47 in an m6A-dependent manner, leading to the activation of the CD47/SIRPα axis. Ultimately, by inhibiting the phagocytic function of TAMs, CD90 mediates immune evasion in GC. In summary, our work highlights the critical role of the CD90-IGF2BP2-CD47 axis in immune evasion in GC. This finding is expected to provide significant experimental evidence for elucidating the pathogenesis of GC and discovering potential molecular targets for clinical treatment.
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高影响因子
BRAIN RESEARCH
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2025
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IF 2.6
Shan Hui,Yi Long,Lemei Zhu,Wei Shi,Qing Zheng,Lihui Liang
Background Alzheimer’s disease (AD) is characterized by cognitive decline and neuronal loss, with cellular senescence emerging as a key driver. The insulin-like growth factor-1 receptor (IGF1R) pathway is implicated in aging and AD pathology. IGF2 mRNA binding protein 2 (IGF2BP2) can stabilize IGF1R mRNA, but its role in AD-associated neuronal senescence remains unclear. Methods We established AD mouse models and H 2 O 2 -induced senescent neuronal cell models to explore the impact of IGF2BP2 in neuronal senescence and cognitive deficits. RNA pull-down assays, methylated RNA immunoprecipitation (MeRIP)-qPCR, and behavioral tests were used to elucidate the molecular mechanisms and therapeutic potential of targeting IGF2BP2. Results IGF2BP2 was significantly up-regulated in the hippocampal neurons of AD mice. This upregulation correlated with increased β-amyloid (Aβ) deposition, neuronal damage, and cognitive impairments. In vitro , IGF2BP2 knockdown in H 2 O 2 -induced senescent neurons reduced IGF1R expression and alleviated neuronal senescence, as evidenced by decreased senescence-associated secretory phenotype factors and improved cell viability. Mechanistically, IGF2BP2 stabilized IGF1R mRNA through m6A modification, enhancing its expression. Knockdown of IGF2BP2 decreased IGF1R mRNA stability and expression, thereby mitigating neuronal senescence. In AD mice, IGF2BP2 knockdown improved cognitive function, reduced Aβ deposition, and delayed neuronal senescence. Conclusion IGF2BP2 contributes to neuronal senescence and cognitive deficits in AD by regulating IGF1R expression through m6A modification.
研究领域:
神经科学
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分子生物学
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表观遗传学
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衰老研究
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神经退行性疾病
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PubMed
高影响因子
FASEB JOURNAL
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2026
·Vol. 40
·期 13
·e72115
·
IF 4.3
Hanjing Song,Jiani Zhang,Suman Huo,Xian Xu,Caiyan Huang,Lin Chen,Xueqin Yang,Yeqing Qian,Xiao-Jing Zhu
The transcription factor p63 is indispensable for epithelial stem cell proliferation/differentiation and epidermal development, with alterations in the p63 pathway underlying a subset of ectodermal dysplasias. Despite its critical role, the mechanisms regulating p63 expression remain poorly understood. Here, we identify an m 6 A-mediated posttranscriptional mechanism controlling the expression of ΔNp63 , the predominant functional p63 isoform in epidermal basal cells. We found that Cre-mediated conditional deletion of Mettl16 , encoding a conserved m 6 A methyltransferase, in mouse epithelial basal cells caused severe skin developmental abnormalities, reminiscent of human ectodermal dysplasias. RNA sequencing revealed significant downregulation of ΔNp63 and its target genes in Mettl16- deficient skin, which linked METTL16 to p63 pathways. Mechanistically, we demonstrated that METTL16 directly binds to ΔNp63 mRNA to mediate its m 6 A modification; this modified ΔNp63 mRNA is subsequently recognized by the m 6 A reader IGF2BP2, which stabilizes ΔNp63 mRNA and thereby modulates its protein levels. Critically, restoration of ΔNp63 expression mitigated the epidermal defects in Mettl16 -deficient mice. Collectively, our findings uncover a novel METTL16-m 6 A-IGF2BP2- ΔNp63 regulatory axis governing epidermal development, providing insights into the etiology of ectodermal dysplasias. Graphical p63 is essential for epithelial stem cell proliferation, differentiation, and epidermal development, and alterations in its pathway are associated with human ectodermal dysplasias. This study identifies a posttranscriptional mechanism whereby METTL16 directly binds to p63 mRNA and adds m6A modifications. The m6A reader IGF2BP2 recognizes these modifications, stabilizes p63 mRNA, and controls p63 protein levels. Together, these findings uncover a METTL16-m6A-IGF2BP2-p63 regulatory axis governing epidermal development, offering new insights into the etiology of human ectodermal dysplasias.
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Advanced Science
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2026
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IF 14.1
Lang Chen,Wenyi Lin,Lang Jiang,Xuehui Gao,Chenyan Yu,Jili Han,Zhenping Liu,Xuefeng Li,Mei He,Chang Li,Qilan Li,Chaoying Song,Jiqian Xu,You Shang
Patients with sepsis exhibit circadian disruption and persistent immunosuppression. However, the molecular mechanisms linking them remain unclear. Integration of multi‐cohort transcriptomic and single‐cell datasets shows that circadian gene dysregulation in patients with sepsis and septic mice correlates with disease severity and immunosuppressive states, with monocytes/macrophages emerging as a principal affected population. Sustained endotoxin stimulation elevates the core clock repressor NR1D1 in macrophages, which occupies the Igf2bp2 promoter and suppresses its transcription. Loss of IGF2BP2 destabilizes the V‐ATPase subunit transcripts Atp6v1b2 and Atp6v0c through an m 6 A‐dependent mechanism, disrupting phagolysosomal acidification rhythms and pathogen clearance. siRNA‐mediated NR1D1 knockdown restores IGF2BP2 expression, circadian oscillations, and phagolysosomal function during the development of endotoxin tolerance. To achieve therapeutic delivery, we engineer hybrid membrane nanovesicles (siNR1D1@HM‐LNP) that reverse circadian and immune dysregulation in septic mice, enhance bacterial clearance, and markedly improve survival. These findings establish an NR1D1‐mediated circadian‐immune coupling mechanism and provide a therapeutic strategy for targeting sepsis‐induced immunosuppression. Sepsis disrupts immune‐cell rhythms and weakens bacterial clearance. Biomimetic nanovesicles combining erythrocyte and inflammation‐activated macrophage membranes deliver siNR1D1 to dysfunctional macrophages, restoring the NR1D1–IGF2BP2–V‐ATPase pathway, circadian regulation, phagolysosomal acidification, and antimicrobial defense. In mouse models of polymicrobial sepsis and secondary pneumonia, treatment improves immune balance and bacterial control, reduces organ injury, and increases survival.
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MOLECULAR NEUROBIOLOGY
·
2024
·
IF 4.6
Shen Yifen,Zhang Le,Yang Tao,Li Xiaosong,Liu Chao,Li Hongmei,Hu Yanping,Shen Hao,Li Hua,Orlov Yuriy L.,Zhou Shasha,Shen Yihang
Puberty onset through hypothalamic-pituitary-gonad (HPG) axis as an important reproductive event in postnatal development is initiated from hypothalamic arcuate nucleus (ARC). The growing evidence indicates that translational control also plays an essential role in the final expression of gonadotropin genes. To investigate the role of protein translation and behavior of ribosomes in pubertal onset, the global profiles of transcriptome, single ribosome (monosome), polysome, and tandem mass tag proteome were comprehensively investigated in rat hypothalamic ARCs of different pubertal stages using RNA sequencing, polyribo sequencing, and mass spectrum. Transcriptome-wide enrichments of N6-methyladenosine and IGF2BP2 were investigated using meRIP and RIP sequencing. Monosome was robustly enriched on a large proportion of mRNA in early puberty rats (postnatal day (PND)-25) compared to late puberty (PND-35 and PND-45). Monosome-enriched mRNAs, including HPG axis-related genes, had a large number of upstream ORFs (uORF, < 100 nt) and displayed translational repression in early puberty. Furthermore, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) could particularly interact with and facilitate monosome to bind with mRNA in early puberty. Finally, ectopic over-expression of IGF2BP2 in hypothalamic ARC via lateral ventricle injection in vivo could recruit monosome to aggregate on mRNA and delay puberty onset. We uncovered a novel regulatory mechanism of IGF2BP2 and monosome for translational control in puberty onset, which shed light on the neuroendocrine regulatory network involved in HPG axis activation.
研究领域:
神经内分泌学
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生殖生物学
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翻译调控
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分子生物学
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高影响因子
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