Advanced Science
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2026
·
IF 14.1
Hui Wang,Mengyu Zhang,Weipeng Gong,Jiaxuan Wu,Junping Zhang,Wenxiu Zhang,Yue Liu,Kui Wang,Canhua Huang,Jun Zhou,Sijin Wu,Yan Li,Tianliang Li
Signal transducer and activator of transcription 3 (STAT3) activation is crucial in intestinal inflammation and tumorigenesis. However, its metabolic regulation is not well understood. Herein, we identified a macrophage-dependent methionine-S-adenosylmethionine (SAM)-protein arginine methyltransferase 1 (PRMT1)-lactate dehydrogenase A (LDHA)-lactate axis that controls intestinal inflammation through STAT3 regulation. Specifically, SAM promoted STAT3 Y705 phosphorylation and upregulated anti-inflammatory interleukin-10 expression in macrophages. Additionally, genetic ablation of PRMT1 in myeloid cells not only impairs STAT3 activation but also exacerbates colitis and promotes inflammation-associated tumorigenesis. Mechanistically, PRMT1 directly methylates LDHA at R268/R269, thereby enhancing its activity and lactate production. Subsequently, the resulting lactate induces STAT3 lactylation at K709, stabilizing an open conformation that facilitates Y705 phosphorylation. Importantly, disruption of this modification through K709-specific inhibition effectively blocks STAT3 activation and, consequently, exacerbates colitis progression. Overall, this study reveals STAT3 lactylation as a novel post-translational modification that integrates methionine metabolism with glycolytic flux to regulate intestinal inflammation, highlighting the critical role of immunometabolism in colonic inflammation.
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iScience
·
2026
·Vol. 29
·期 6
·
IF 4.5
Haochang Song,Meng Yang,Shengquan Wu,Qihui Dai,Weihong Qin,Weiheng Xie,Yuzhi Chen,Xiaoyun Jiang,Xiaojun Zhang,Xiuqin Deng,Chuang Ouyang,Yunman Zhang,Xinguang Liu,Yingjie Zhu,Gonghua Huang
Andrographolide (AP), a diterpenoid extracted from Andrographis paniculata , has emerged as a promising treatment for Alzheimer’s disease (AD) in preclinical studies, but the underlying mechanisms remain incompletely defined. Here, we demonstrated that AP treatment improved cognition performance and reduced amyloid-β (Aβ) plaque accumulation in 5×FAD transgenic mice of both sexes, by mitigating microglial senescence. Proteomic analysis revealed that AP markedly decreased cholesterol content in the cerebral cortex. Using an in vitro low-density lipoprotein-induced senescence model, we found that AP significantly alleviated senescence in BV2 microglia while enhancing their phagocytic capacity. Mechanistically, AP mitigated microglial senescence by inhibiting STAT3 signaling. Overall, these findings identify a previously unrecognized immunometabolic mechanism for AP in the treatment of AD.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2025
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IF 5.6
Hailun Zheng,Xiaoyan Mao,Zhiwei Chen,Linying Wang,Fuxiang Shangguan,Zihao Tao,Jinyao Ye,Weilan Cao,Qing Yao,Lili Yan,Ruijie Chen,Shihui Bao,Longfa Kou
Chemotherapy remains one of the main treatments for gastric cancer, but the efficacy of 5-fluorouracil (5-FU) is limited by drug resistance. Ferroptosis is a unique mode of regulated cell death characterized by iron accumulation and lipid peroxidation, and its induction by aberrant STAT3 signaling may contribute to chemotherapy resistance. Cryptotanshinone (Cpt) is a bioactive compound extracted from Salvia miltiorrhiza that acts as a STAT3 inhibitor and has shown efficacy against several malignancies, endowing its potential as an agent to overcome the chemotherapy of gastric cancer. Importantly, cancer cells—especially drug-resistant cells—often upregulate amino acid transporters to import indispensable nutrients that support rapid proliferation, and therefore these transporters could guide the target delivery of chemotherapeutics for enhanced delivery efficiency. Here, we developed an amino acid transporter-targeted nanoplatform (F/C@Trp-NPs) co-loaded with 5-FU and Cpt to target the SLC6A14 (ATB 0,+ ) transporter, which is abnormally upregulated in gastric cancer cells, and evaluated its anticancer effects. The F/C@Trp-NPs significantly inhibited gastric cancer cell proliferation in vitro, consistent with the in vivo results. This study provides a promising new therapeutic strategy for gastric cancer.
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Fundamental Research
·
2025
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IF 6.3
Li Xu,Xinyi Wang,Huiming Xu,Siqi Chen,Wei Jiang,Haoyang Li,Shabbir Khan Afridi,Yuge Wang,Wenjing Luo,Hui Yang,Changyong Tang,Wei Qiu
Abundant evidence indicates that the interaction between astrocytes and microglia through the C3-C3a receptor (C3aR) pathway is a crucial contributor to the pathogenesis of neurodegenerative and autoimmune disorders, such as neuromyelitis optica (NMO). However, the role of C3aR in microglia in modulating inflammation related to local lesions and neurological dysfunctions in NMO remains unclear. In this study, we reveal for the first time that the expression of C3aR on microglia is positively correlated with microglial activation, proinflammatory cytokine secretion, and complement deposition, which results in the typical NMO-like lesion characterized by astrocyte injury with aquaporin 4 (AQP4) loss, demyelination, and motor neuron loss, as well as cognitive impairments, visual defects, and locomotor deficits in different models of NMO. The knockdown of C3aR or the use of a C3aR antagonist, both ex vivo and in vivo , effectively attenuates neuroinflammation, alleviates pathological lesions, and rescues neurological functions. Mechanistically, we identify STAT3 as a downstream target of microglial C3aR signalling that functionally mediates NMO pathogenesis. Blocking the C3aR/STAT3 cascade restores motor and visual functions by reducing the release of proinflammatory factors. Taken together, our study demonstrates a key role of the C3aR-STAT3 pathway in regulating neuroinflammation in NMO pathology and provides potential targets for therapeutic intervention.
研究领域:
神经免疫学
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神经科学
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自身免疫性疾病
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分子信号传导
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PHYTOMEDICINE
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2026
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IF 11.3
Jieli Pan,Jinjun Ji,Xingpan Xin,Yihong Gan,Zixin Huang,Jing Chen,Ying Li,Jie Bao,Yujun Tang,Chengping Wen,Li Xu
Background Systemic lupus erythematosus (SLE) is an autoimmune disease with marked female predominance. Lupus nephritis (LN), one of its most severe manifestations, is strongly associated with aberrant activation of signal transducer and activator of transcription 3 (STAT3). Estrogen receptor β (ERβ) has been reported to exert immunoregulatory effects, but its role in restraining STAT3 signaling in LN remains unclear. Purpose This study aimed to investigate whether genistein, a phytoestrogen with selective affinity for ERβ, can modulate the ERβ–STAT3 axis to attenuate lupus nephritis. Methods The therapeutic effects of genistein were evaluated in MRL/lpr and pristane-induced lupus mouse models and in LPS-stimulated macrophages. Macrophage polarization, oxidative stress, mitochondrial function, and ERβ–STAT3 signaling were assessed using flow cytometry, biochemical assays, immunoblotting, and bioinformatic analyses. Results Genistein significantly ameliorated renal injury, reduced proteinuria, and decreased serum autoantibody and IL-6 levels in lupus models. Mechanistically, genistein suppressed M1 macrophage polarization by activating ERβ and inhibiting STAT3 and NF-κB signaling. Genistein also attenuated oxidative stress by preserving mitochondrial membrane potential, reducing reactive oxygen species production, and restoring antioxidant capacity. Pharmacological blockade of ERβ markedly attenuated the anti-inflammatory effects of genistein, confirming ERβ-dependent regulation of STAT3 signaling. Conclusion This study identifies ERβ as a negative regulator of STAT3-driven inflammation and demonstrates that genistein therapeutically engages this axis to suppress macrophage-mediated renal injury, offering a promising therapeutic strategy for lupus nephritis.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2023
·Vol. 24
·期 19
·14532
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IF 5.6
Ji-Rong Xie,Xiao-Jie Chen,Gang Zhou
Oral squamous cell carcinoma (OSCC) poses a significant obstacle to the worldwide healthcare system. Discovering efficient and non-toxic medications is crucial for managing OSCC. Nuciferine, an alkaloid with an aromatic ring, is present in the leaves ofNelumbo nucifera. It has been proven to play a role in multiple biological processes, including the inhibition of inflammation, regulation of the immune system, formation of osteoclasts, and suppression of tumors. Despite the demonstrated inhibitory effects of nuciferine on different types of cancer, there is still a need for further investigation into the therapeutic effects and potential mechanisms of nuciferine in OSCC. Through a series of in vitro experiments, it was confirmed that nuciferine hindered the growth, movement, and infiltration, while enhancing the programmed cell death of OSCC cells. Furthermore, the administration of nuciferine significantly suppressed the signal transducer and activator of transcription 3 (STAT3) signaling pathway in comparison to other signaling pathways. Moreover, the activation of the STAT3 signaling pathway by colivelin resulted in the reversal of nuciferine-suppressed OSCC behaviors. In vivo, we also showed the anti-OSCC impact of nuciferine using the cell-based xenograft (CDX) model in nude mice. Nonetheless, colivelin diminished the tumor-inhibiting impact of nuciferine, suggesting that nuciferine might partially impede the advancement of OSCC by suppressing the STAT3 signaling pathway. Overall, this research could offer a fresh alternative for the pharmaceutical management of OSCC.Keywords:cell-derived xenograft;nuciferine;oral squamous cell carcinoma;signal transducer and activator of transcription 3;tumor growth
研究领域:
肿瘤学
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药理学
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分子生物学
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ARCHIVES OF PHARMACAL RESEARCH
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2023
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IF 6.7
Song Xiaoping,Wang Lina,Tang Wei,Yuan Luyao,Liu Qingchao,Li Jing,Fan Daidi
Gefitinib, as the first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has achieved great advances in the treatment of non-small cell lung cancer (NSCLC), but drug resistance will inevitably occur. Therefore, exploring the resistance mechanism of gefitinib and developing new combination treatment strategies are of great importance. In our study, the results showed that selumetinib (AZD6244) synergistically inhibited the proliferation of NSCLC with gefitinib. Selumetinib also enhanced gefitinib-induced apoptosis and migration inhibition ability in gefitinib-resistant lung cancer cell lines. Subsequently, the negative regulation between MIG6 and STAT3 was observed and verified through the STRING database and western blotting assays. Sustained activation of STAT3 was significantly downregulated when co-treatment with selumetinib in gefitinib-resistant cells. However, the downregulation of p-STAT3, resulting from the combination of selumetinib and gefitinib was counteracted by the deletion of MIG6, suggesting that selumetinib enhanced gefitinib sensitivity by regulating MIG6/STAT3 in NSCLC. In contrast, p-STAT3 was further inhibited after treatment with gefitinib and selumetinib when MIG6 was overexpressed. Furthermore, the combined administration of selumetinib and gefitinib effectively promoted the sensitivity of lung cancer xenografts to gefitinib in vivo, and the tumor inhibition rate reached 81.49%, while the tumor inhibition rate of the gefitinib monotherapy group was only 31.95%. Overall, MIG6/STAT3 negative regulation plays an important role in the sustained activation of STAT3 and the resistance to EGFR-TKIs. Our study also suggests that EGFR-TKIs combined with MEK1/2 inhibitors, such as selumetinib, may be beneficial to those NSCLC patients who develop a primary or acquired resistance to EGFR-TKIs, providing theoretical support for combining TKIs and selumetinib in clinical cancer treatment.
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LIFE SCIENCES
·
2021
·
IF 5.037
Rui Huang,Qixia Yang,Tiantian Wang
Aims Norcantharidin (NCTD) exhibits antitumor, anti-inflammatory, and anti-fibrosis properties, which makes NCTD an attractive candidate for the treatment of pathological scars. This study was designed to investigate the potential effects of NCTD on fibroblast proliferation and explore the underlying mechanisms. Materials and methods First, cell viability and cell apoptosis were evaluated to determine the effects of NCTD on human skin fibroblasts, at 10, 50, and 100 μM. To explore the mechanism, bioinformatics analyses, chromatin immunoprecipitation, RNA immunoprecipitation, and RNA pulldown assays, and luciferase reporter assays were performed to verify the relationships among NCTD, signal transducer and activator of transcription 3 (STAT3), annexin A2 pseudogene 2 (ANXA2P2), and ubiquitin-associated protein 2-like (UBAP2L) mRNA in fibroblasts. Loss-of-function experiments were performed to investigate the roles played by STAT3, ANXA2P2, and UBAP2L in the proliferation and apoptosis of fibroblasts. Key findings We found that NCTD administration induced fibroblast apoptosis and inhibited fibroblast proliferation in a dose-dependent manner. Mechanistically, NCTD inhibited ANXA2P2 transcription through the inhibition of STAT3 phosphorylation. Subsequently, ANXA2P2 was found to enhance the physical interaction between UBAP2L mRNA and lin-28 homolog B (LIN28B), which increased the stability and levels of UBAP2L mRNA. Loss-of-function assays demonstrated that ANXA2P2 and UBAP2L knockdown induced fibroblast apoptosis and suppressed fibroblast proliferation. Significance In conclusion, we confirmed that NCTD inhibits fibroblast proliferation by inhibiting the STAT3/ANXA2P2/UBAP2L axis, which suggested that NCTD could represent a new candidate for the treatment of pathological scars.
研究领域:
药理学
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细胞生物学
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分子生物学
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病理学
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2021
·
IF 5.051
Shaohua Xu,Ruolan Fan,Lu Wang,Weishen He,Haixia Ge,Hailan Chen,Wen Xu,Jian Zhang,Wei Xu,Yaqian Feng,Zhimin Fan
Using STAT3 inhibitors as a potential strategy in cancer therapy have attracted much attention. Recently, celastrol has been reported that it could directly bind to and suppress the activity of STAT3 in the cardiac dysfunction model. To explore more effective STAT3 inhibiting anti-tumour drug candidates, we synthesised a series of celastrol derivatives and biologically evaluated them with several human cancer cell lines. The western blotting analysis showed that compound 4 m, the most active derivative, could suppress the STAT3’s phosphorylation as well as its downstream genes. SPR analysis, molecular docking and dynamics simulations’ results indicated that the 4m could bind with STAT3 protein more tightly than celastrol. Then we found that the 4m could block cell-cycle and induce apoptosis on HCT-116 cells. Furthermore, the anti-tumour effect of 4m was verified on colorectal cancer organoid. This is the first research that discovered effective STAT3 inhibitors as potent anti-tumour agents from celastrol derivatives.
研究领域:
肿瘤学
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药理学
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分子生物学
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2015
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IF 4.152
Yunchun Zhao,Caihong Zheng,Li Zhang,Yue Chen,Yiqing Ye,Mengdan Zhao
Biodegradable and biocompatible poly( d,l -lactic- co -glycolic acid) (PLGA)was conjugated to the 5′-thiol end of signal transducer and activator of transcription 3 (STAT3) small interfering RNA (STAT3–siRNA) via a disulfide bond. In aqueous environments, these siRNA–PLGA conjugates can spontaneously form core/shell type spherical micelles with a particle size of about 200 nm. A biodegradable, low molecular weight cationic polymer, chitosan oligosaccharide (CSO), was added to the siRNA–PLGA micelles at different nitrogen to phosphate (N/P) ratios to form stable, spherical siRNA–PLGA/CSO micelles with sizes of 150–180 nm. The siRNA–PLGA/CSO micelles were produced via ionic complexation between negatively charged siRNA and positively charged CSO on the outer shell of the micelles. The siRNA–PLGA/CSO micelles exhibited superior cellular uptake and STAT3 gene silencing efficiency in SKOV3 ovarian cancer cells when compared with siRNA/CSO complexes at the same N/P ratios with no significant differences with lipofectamine 2000. Furthermore, the siRNA–PLGA/CSO micelles showed that the efficiencies of cellular uptake and STAT3 gene silencing gradually increased with increasing N/P ratios. The siRNA–PLGA/CSO micelles also inhibited the growth of SKOV3 cells, as well as, promoted apoptosis of the cells. These results indicate that siRNA–PLGA/CSO micelles can be utilized as a novel and efficient siRNA carrier to treat a variety of diseases.
研究领域:
癌症研究
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药学
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纳米技术
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分子生物学
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Oxidative Medicine and Cellular Longevity
·
2022
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IF 7.31
Fei Jia,Yu Liu,Xinyu Dou,Chuanchao Du,Tianli Mao,Xiaoguang Liu
Osteosarcoma (OS) is the most common malignancy of bone. Liensinine exerts antitumor effects on cancers of the colon, breast, and gallbladder. However, its antitumor activity in OS remains unclear. This study is aimed at investigating the efficacy of liensinine against OS and the underlying mechanism of action. Cell proliferation, apoptosis, and cycle arrest in OS were detected using the Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays, respectively. The production of reactive oxygen species (ROS), glutathione (GSH) and glutathione disulfide (GSSG) concentrations, and mitochondrial membrane potential (MMP) of OS cells were measured by flow cytometry, colorimetry, and JC-1 staining. The expressions of factors related to apoptosis, cell cycle, and activation of the JAK2/STAT3 pathway were determined by Western blotting. To examine the potential role of ROS, an antioxidant (N-acetyl cysteine, NAC) was used in combination with liensinine. In vivo, we generated a xenograft mouse model to assess its antitumor efficacy. Tissue level expressions of factors related to apoptosis and activation of the JAK2/STAT3 pathway were assessed by immunohistochemistry or Western blotting. Liensinine inhibited the proliferation and induced G0/G1 phase arrest and apoptosis of OS cells in a dose-dependent manner. Additionally, liensinine promoted intracellular ROS production, enhanced the GSSG/GSH ratio, and induced MMP loss and ROS-mediated suppression of the JAK2/STAT3 pathway. NAC significantly attenuated the liensinine-induced antitumor activities and activated the JAK2/STAT3 pathway. In vivo, liensinine effectively inhibited the OS growth and promoted apoptosis; however, it had no negative effect on the internal organs. In conclusion, liensinine-induced ROS production could suppress the activation of the JAK2/STAT3 pathway and inhibit the OS growth both in vivo and in vitro. Our findings provided a new rationale for subsequent academic and clinical research on OS treatment.
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TOXICOLOGY MECHANISMS AND METHODS
·
2021
·
IF 2.987
Weiya Cao,Yinci Zhang,Amin Li,Pan Yu,Li Song,Jiaojiao Liang,Niandie Cao,Jiafeng Gao,Ruyue Xu,Yongfang Ma,Xiaolong Tang
Objective Epithelial mesenchymal transition (EMT) and inflammation have been identified as carcinogenic agents. This study aims to investigate whether inhibition of trichloroethylene (TCE) associated hepatocellular carcinoma (HCC) by curcumin is associated with inflammation and EMT.Methods In the current study, TCE sub-chronic cell model was induced in vitro, and the effects of TCE on cell proliferation, migration, invasion, and expression of functional proteins were verified by Western blot, MTT, clone formation, wound healing, Transwell. The detoxification effect of curcumin on TCE was explored by a mouse tumor-bearing experiment.Results TCE induces hepatocyte migration, colony formation, and EMT in vitro. In vivo studies have shown that curcumin significantly reduces the mortality of mice and control the occurrence and size of liver tumors by inhibiting the IL-6/STAT3 signaling pathway. In vitro, curcumin inhibits the proliferation of HepG2 cells as determined by MTT assay. In addition, curcumin significantly inhibited the protein expression of IL-6R, STAT3, snail, survivin, and cyclin D1 in THLE-2 and HepG2 cells induced by IL-6.Conclusion Curcumin has anti-inflammatory and anti-proliferative effects, and inhibits the development of HCC induced by TCE by reversing IL-6/STAT3 mediated EMT.
研究领域:
药理学
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肿瘤学
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分子生物学
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高影响因子
危险品化学品经营许可证（带存储）