JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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2026
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IF 4.3
Zihang Yuan,Jie Wang,Haoran Zhang,Yingying Miao,Yuanyuan Chai,Anqin Li,Qianhui Tang,Qingyu Chen,Luyong Zhang,Qinwei Yu,Zhenzhou Jiang
Effective first-line treatments for cholestasis are limited, leading to poor outcomes and liver transplantation after ursodeoxycholic (UDCA)/obeticholic acid (OCA) intolerance. We investigated the role of cholangiocyte sphingosine-1-phosphate receptor 1 (S1PR1) in cholestasis pathogenesis to identify new therapeutic targets. We generated cholangiocyte-specific S1pr1 knockout mice ( S1pr1 ΔIBEC ). Cholestasis models included bile duct ligation (BDL) (14 days) and 0.5% cholic acid (CA) diet (4 months). The level of Sphingosine-1-phosphate (S1P) and its receptor, especially S1PR1 in cholangiocytes were significantly increased in both BDL or 0.5% CA diet models. Sphingosine kinase 1 (SphK1)-derived S1P from hepatic stellate cells (HSCs)/endothelial cells activated cholangiocyte S1PR1, promoting Stat3 phosphorylation and releasing interleukin-6 (IL-6)/C-C motif chemokine (CCL) 7, which remodeled the inflammatory microenvironment and exacerbated liver injury. S1PR1 deletion significantly reduced liver injury, fibrosis, and inflammation. Likewise, treatment with a specific inhibitor of cholangiocyte S1PR1, W146, slightly improved liver injury induced by BDL. The functional effect of S1PR1 in cholangiocyte was further strengthened by our design of the nanoparticle-delivered W146. This demonstrated that cholangiocytes-specific deletion of S1PR1 can alleviate liver fibrosis and injury caused by biliary obstruction or chronic cholestasis, which helps to develop S1PR1 as a target for the treatment of liver fibrosis and cholestasis.
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NEUROPHARMACOLOGY
·
2026
·
IF 4.7
Ruinan Ni,Shulin Bi,Zhihong Cheng,Shangqi Ni,Yang Guo,Yu Xiang,Bin Peng
Neuropathic pain (NP) remains a clinical challenge due to the limited efficacy and significant side effects of current treatments, highlighting the need for a deeper understanding of its pathogenesis. While dysfunction of GABAergic inhibitory neurons in the spinal dorsal horn is a known key driver of central sensitization, the mechanisms precipitating this neuronal injury remain obscure. In this study, using a spinal nerve ligation (SNL) model, we aimed to investigate whether the chemokine CXCL10 drives NP progression by promoting ferroptosis, a process that is associated with and ultimately leads to the loss of GABAergic neurons. We observed that mechanical hypersensitivity in post-SNL rats coincided with progressive spinal ferroptosis, characterized by iron accumulation, lipid peroxidation, and suppression of the GPX4/xCT system. Notably, CXCL10 expression mirrored the trajectory of ferroptosis. Interventional studies established CXCL10 as an upstream initiator, rather than a consequence, of the ferroptotic process. Mechanistically, we demonstrated that CXCL10 activates STAT3 through the CXCR3 receptor; activated STAT3 then acts as a transcriptional repressor to downregulate the cystine transporter xCT, thereby triggering ferroptosis. This molecular cascade resulted in a significant loss of spinal GABAergic neurons, which could be partially reversed by CXCL10 inhibition. Collectively, our findings uncover a novel mechanism of NP maintenance, wherein the CXCL10/CXCR3/STAT3 axis disrupts the spinal excitation-inhibition balance by promoting ferroptosis-mediated loss of inhibitory neurons. These results offer a fresh perspective on NP pathology and identify this signaling axis as a promising therapeutic target.
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JOURNAL OF APPLIED TOXICOLOGY
·
2026
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IF 3.1
Yanping Lu,Yaqi Li,Yuqi Tong,Lian Huang,Zhaohui Zhang
Beryllium is widely used in nuclear technology, aerospace, and defense. Long-term beryllium exposure causes chronic beryllium disease (CBD) characterized predominantly by pulmonary fibrosis. Cellular senescence is an important mechanism underlying pulmonary fibrosis, and the IL-6/STAT3 pathway has been implicated as a central axis linking inflammation, senescence, and tissue remodeling. However, whether this pathway promotes beryllium sulfate (BeSO 4 )–induced pulmonary fibrosis through regulation of senescence remains unclear. Herein, Sprague–Dawley rats were exposed to BeSO 4 , and hematoxylin–eosin (H&E) and Masson's trichrome staining were used to assess lung injury and fibrosis. Immunohistochemistry (IHC) assays were used to assess fibrosis-related factors, pathway molecules, and senescence markers in the lung tissues. In vitro, A549 cells were pretreated with the IL-6/STAT3 inhibitor LMT-28 before BeSO 4 exposure, and alterations in cell morphology, proliferation, senescence-related markers, and fibrosis-related markers were evaluated. The results demonstrated that BeSO 4 exposure promoted cellular senescence and pulmonary fibrogenesis via activating IL-6/STAT3 signaling, whereas LMT-28 treatment significantly attenuated these processes. These findings elucidate the molecular mechanism by which BeSO 4 induces pulmonary fibrosis through cellular aging, providing a basis for the discovery of potential therapeutic targets.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Jia-Qi Yang,Shu-Ya Li,Peng Jiang,Guo-Li Wu,Zheng Luo,Xin Guo,Xue-Kun Liu,Hai-Ming Sun,Yu-Chen Jiang
Ethnopharmacological relevance Asarum heterotropoides F. Schmidt, a classic Chinese herb, traditionally treats liver deficiency with its pungent, warm nature and liver-qi smoothing properties. Asarinin (ASA), an abundant and characteristic lignan in Asarum, has the potential to protect the liver and has shown measurable systemic exposure in the body, making it a key candidate for verifying this traditional use. Aim of the study We aim to delineate the molecular mechanisms underlying the hepatoprotective activity of ASA. Materials and methods Liver injury and fibrosis was generated in C57BL/6 mice by intraperitoneal TAA and CCL 4 , with oral ASA treatment. To investigate the mechanisms, neutrophil depletion and TRα knockdown approaches were employed. LX-2 were activated using TGF-β and co-cultured by ASA, neutrophils, and/or conditioned medium from primary hepatocytes; TRα was silenced via siRNA. Results The findings indicate that ASA alleviates hepatic fibrosis by reducing extracellular matrix deposition, inflammation, EMT, and neutrophil extracellular traps through TRα-STAT3 signaling pathway. Loss of TRα exacerbates fibrotic progression, whereas neutrophil ablation attenuates pathology. In vitro , ASA modulates ECM composition, inflammatory cytokine levels, and EMT-related processes in activated hepatic stellate cells. These effects are mediated through TRα and STAT3 signaling, as TRα knockdown diminishes the regulatory influence of ASA on LX-2 activation. RNA sequencing was used to verify the relevant mechanisms. ASA exerts potent anti-fibrotic effects by disrupting intercellular crosstalk and modulating the TRα-STAT3 signaling axis. Conclusions The therapeutic efficacy of ASA against liver fibrosis may hinge on its ability to target TRα-dependent STAT3 activation, thereby reshaping the hepatic microenvironment.
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Cell Reports Medicine
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2026
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IF 14
Zifan Pei,Yifan Yin,Nailin Yang,Shumin Sun,Nan Jiang,Fangyi Yu,Xiaofen Zhang,Jihu Nie,Youdong Chen,Longxiao Li,Jie Wu,Fei Gong,Minming Chen,Wei Liu,Liang Cheng
Clinical evidence has suggested that persistent STAT3 activation and alteration in lipid metabolism correlate with pathological progression in patients with breast cancer, driving resistance to chemotherapy. Herein, we show that H 2 S, an endogenous gas signaling molecule, sensitizes breast cancer to chemotherapy by suppressing STAT3 signaling-mediated lipid metabolism and improves tumor immunogenicity. Moreover, we further identify Ni 2+ as immune agonist for potent metalloimmunotherapy. The construction of an activable nanoplatform enables the controllable delivery of metal ions and H 2 S gas, which triggers pyroptosis and mobilizes multiple immune cells to elicit systemic anti-tumor immunity in combination with chemotherapy. Moreover, the synergy with αPD-1 inhibits the progression of both primary and metastatic tumors. Our work highlights the potential of bioactive gas transmitters and nutrient metal ions for reversing the dual dilemmas of chemoresistance and low immunogenicity in breast cancer and thus provides a nanosensitization strategy to synergize with multiple clinical treatment modalities.
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TISSUE & CELL
·
2025
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IF 2.5
Minhui Wang,Daojun Chen,Daofa Zhang,Hui Han,Maowei Xie,Ying Zhang,Yun Cao,Jiali Wei
Background Renal fibrosis (RF) is a common histopathological feature of chronic kidney disease (CKD) and is closely associated with persistent inflammation and regulated cell death. However, the underlying molecular mechanisms of pyroptosis in RF are unclear. Methods Pyroptosis-related hub genes in RF were identified through bioinformatics analysis. Granzyme B ( GZMB ) was knocked down in transforming growth factor (TGF-β)-stimulated HK-2 cells and in a folic acid (FA)-induced nephropathy mouse model. Western blot and enzyme-linked immunosorbent assays were performed to detect the expression of fibrosis and pyroptosis-related markers. Cell viability was assessed by the Cell Counting Kit-8 assay. Hematoxylin and eosin (HE) and Masson's staining were used to evaluate tubular injury and collagen deposition in renal tissues. Results GZMB was identified as a pyroptosis-associated hub gene. It was significantly upregulated in RF and exhibited high diagnostic performance. In TGF-β-stimulated HK-2 cells, GZMB knockdown enhanced cell viability and reduced lactate dehydrogenase release. In vivo , GZMB silencing ameliorated tubular injury, reduced collagen deposition, and improved renal function. The expression levels of pyroptosis-related proteins, including the N-terminal fragment of gasdermin D, cleaved caspase-1, and NOD-like receptor family pyrin domain containing 3 (NLRP3), as well as fibrotic markers alpha-smooth muscle actin and collagen type I, were downregulated after GZMB knockdown. Mechanically, GZMB knockdown inhibited NLRP3 inflammasome activation and suppressed the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. Conclusion GZMB deficiency inhibits pyroptosis and dampens the JAK2/STAT3 pathway, representing a potential approach for RF treatment.
研究领域:
肾脏病学
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分子生物学
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细胞信号传导
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炎症
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纤维化研究
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高影响因子
Biomolecules
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2025
·Vol. 15
·期 12
·1749
·
IF 4.8
Lingyan Chen,Dejian Chen,Fengzhuo Yang,Xinyi Chen,Binjiao Zheng
Background: Breast cancer remains the most common malignancy among women worldwide. Current systemic treatment strategies include chemotherapy, immunotherapy, bone-stabilizing agents, endocrine therapy for hormone receptor-positive disease, anti-HER2 therapy for HER2-positive disease, and poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA mutation cases. However, effectively overcoming drug resistance and reducing recurrence and metastasis rates remain major therapeutic challenges. Methods: To investigate the underlying mechanism of RSL3 in PARPi-resistant breast cancer cells, we treated several PARPi-resistant breast cancer cells with varying doses of RSL3. The regulatory proteins of STAT3 were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Immunoprecipitation and ubiquitination assay were performed to identify the STAT3 ubiquitination levels. Results: Recently, we identified that RSL3, a ferroptosis activator, exhibits potent antitumor activity against PARPi-resistant breast cancer. Yet, its underlying mechanism remains unclear. Here, we demonstrate that RSL3 directly targets STAT3 and promotes its degradation via the ubiquitination pathway, leading to increased LC3-II levels and decreased p62 expression. These changes ultimately enhance autophagy, which at least partially contributes to elevated apoptosis. Rescue experiments confirmed that STAT3 overexpression reverses RSL3-induced autophagy and apoptosis. Conclusions: Our findings highlight RSL3 as a promising therapeutic agent and STAT3 as a potential target for treating PARPi-resistant breast cancer.
研究领域:
肿瘤学
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分子生物学
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癌症治疗学
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细胞信号传导
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Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-9
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IF 6.1
Zheng Rongji,Guan Tian,Hong Chaoqun,Yao Yao,Fang Yutong,Huang Wei,Chen Chunfa,Zeng Huancheng,Huang Jiman,Lin Hui,Chen Bingfeng,Zhang Rendong,Chen Dongmei,Ding Zhechun,Zeng Haoyu,Wu Jundong
ObjectivesSTAT3 is a transcriptional activator of breast cancer oncogenes, suggesting that it could be a potential therapeutic target for breast cancer. Therefore, this study investigated the potential application of C188-9, a STAT3 signal pathway inhibitor, in the treatment of breast cancer through a novel pre-clinical platform with patient-specific primary cells (PSPCs).Methods PSPCs were isolated from breast cancer samples obtained via biopsy or surgery from fifteen patient donors with their full acknowledgements. PSPCs were treated with C188-9 or other chemotherapeutic agents, and then analyzed with cell viability assay. Western blot assay and real-time quantitative PCR were also used to determine the expression and activity of STAT3 signaling pathway of corresponding PSPCs.Results C188-9 treatment at normal (experimental) concentration had valid inhibition on PSPCs proliferation. Meanwhile, treatment at a low (clinic-relevant) concentration of C188-9 for an extended period reduced cell viability of PSPCs still more than some of other traditional chemotherapy drugs. In addition, C188-9 decreased expression level of pSTAT3 in PSPCs from some, but not all patient samples. The treatment of C188-9 reduced cell viability of the breast cancer samples through inhibiting the STAT3 to C-myc signaling pathway.Conclusion sIn this study, we tested a novel drug C188-9 at a low, clinic-relevant concentration, together with several traditional chemotherapy agents. PSPCs from ten out of fifteen patient donors were sensitive to C188-9, while some of traditional chemotherapy agents failed. This finding suggested that C188-9 could have treatment effects only on those ten PSPC patient donors, indicating the future personalized utilization of PSPCs.
研究领域:
肿瘤学
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分子生物学
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转化医学
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2017
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IF 2.466
Fan Chen,Dandan Chen,Yubin Zhang,Liang Jin,Han Zhang,Miyang Wan,Tianshu Pan,Xiaochuan Wang,Yuheng Su,Yitao Xu,Junmei Ye
Interleukin-6 (IL-6) signaling is critical for cardiomyocyte hypertrophy, while the role of IL-6 in the pathogenesis of myocardium hypertrophy remains controversial. To determine the essential role of IL-6 signaling for the cardiac development during AngII-induced hypertension, and to elucidate the mechanisms, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were infused subcutaneously with either vehicle or AngII (1.5 μg/h/mouse) for 1 week. Immunohistological and serum studies revealed that the extents of cardiac fibrosis, inflammation and apoptosis were reduced in IL-6 KO heart during AngII-stimulation, while cardiac hypertrophy was obviously induced. To investigate the underlying mechanisms, by using myocardial tissue and neonatal cardiomyocytes, we observed that IL-6/STAT3 signaling was activated under the stimulation of AngII both in vivo and in vitro . Further investigation suggested that STAT3 activation enhances the inhibitory effect of EndoG on MEF2A and hampers cardiomyocyte hypertrophy. Our study is the first to show the important role of IL-6 in regulating cardiac pathogenesis via inflammation and apoptosis during AngII-induced hypertension. We also provide a novel link between IL-6/STAT3 and EndoG/MEF2A pathway that affects cardiac hypertrophy during AngII stimulation.
研究领域:
心脏病学
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免疫学
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分子生物学
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2023
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IF 5
Limin Chai,Qingting Wang,Yan Wang,Danyang Li,Qianqian Zhang,Yuqian Chen,Jin Liu,Huan Chen,Yuanjie Qiu,Nirui Shen,Jian Wang,Xinming Xie,Manxiang Li
To address the molecular mechanisms underlying macrophage migration inhibitory factor (MIF) induced pulmonary artery smooth muscle cells (PASMCs) proliferation, migration and vascular remodeling in pulmonary hypertension (PH), primary cultured rat PASMCs and monocrotaline (MCT)-induced rats with PH were applied in the present study. The results showed that MIF increased signal transducer and activator of transcription 3 (STAT3) phosphorylation, and then stimulated activating transcription factor 6 (ATF6) activation, subsequently triggered autophagy activation, which further led to programmed cell death factor 4 (PDCD4) lysosomal degradation, and eventually promoted PASMCs proliferation/migration. In lung tissues of MCT rats, MIF protein expression was elevated, phosphorylation of STAT3 and activation of ATF6 were increased, activation of autophagy was evident, and reduction of PDCD4 was observed. Intervention with MIF inhibitor 4-Iodo-6-phenylpyrimidine (4-IPP), ATF6 blocker melatonin or autophagy inhibitor chloroquine, confirmed the in vitro interaction among MIF, STAT3, ATF6, autophagy and PDCD4 in MCT induced rats with PH. Targeting MIF/STAT3/ATF6/autophagy/PDCD4 axis effectively prevented the development of PH by suppressing PASMCs proliferation and vascular remodeling. In conclusions, we demonstrate that MIF activates the STAT3/ATF6/autophagy cascade and then degrades PDCD4 leading to PASMCs proliferation/migration and pulmonary vascular remodeling, suggesting that intervention this axis might have potential value in management of PH.
研究领域:
心血管疾病
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分子生物学
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药理学
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JOURNAL OF ETHNOPHARMACOLOGY
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2021
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IF 4.36
Le Shi,Ziqiao Yuan,Jing Liu,Rui Cai,Muhammad Hasnat,Hui Yu,Jing Feng,Zhanglian Wang,Qianqian Zhao,Min Wu,Xinxin Huang,Fei Shen,Lian Yin,Yun Yu,Tao Liang
Ethnopharmacological relevance Modified Simiaowan (MSW) is a traditional Chinese medicine formula that is composed of six herbs. It has been widely used in the treatment of gouty arthritis. Aim of the study This study was designed to investigate the effect of MSW on gouty arthritis and explore the possible mechanisms. Material and methods The rat gouty arthritis model was established by intra-articular injection of Monosodium Urate (MSU) crystal, and then treated with MSW for 5 days. The perimeter of the knee joints was measured in a time-dependent manner and serum samples were collected for the detection of TNF-α, IL-1β, and IL-6 protein levels by ELISA . The protein expressions of MMP-3, TIMP-3, STAT3, and p-STAT3 in cartilage tissues and C28/I2 cells were detected by Western blot , and the levels of proteoglycan in primary chondrocytes and cartilage tissues were determined by toluidine blue staining. In addition, AG490 and IL-6 were used in vitro to explore the function of IL-6/STAT3 pathway in the protective effect of MSU. Results MSW reduced the joint swelling rate in gouty arthritis model and inhibited MSU induced up-regulation of IL-1β, TNF-α, and IL-6 protein levels in serum and synovial fluid. IL-1β induced an increase in p-STAT3 and MMP-3 protein expression in C28/I2 cells, as well as a decrease in TIMP-3. MSW serum inhibited the protein expression changes induced by IL-1β in vitro . Furthermore, inhibition of STAT3 signaling negated the effect of MSW serum on p-STAT3, MMP-3, and TIMP-3 protein levels in C28/I2 cells. MSW also increased the content of proteoglycan significantly both in vivo and in vitro . Conclusion Our data indicated that MSW protected rats from MSU-induced experimental gouty arthritis and IL-1β/IL-6/STAT3 pathway played an essential role in the protective effect of MSU against GA.
研究领域:
药理学
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免疫学
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风湿病学
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中医
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高影响因子
Oncology Letters
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2019
·Vol. 17
·期 5
·4505-4513
·
IF 1.871
Jian Jiang,Yaodong Chen,Tianxiu Dong,Minlu Yue,Yu Zhang,Tingting An,Jiuwei Zhang,Pengfei Liu,Xiuhua Yang
Polydatin, extracted from Polygonum cuspidatum, is known for its anti‑platelet aggregation and anti‑inflammatory effects. However, studies on the association of polydatin with cancer are limited, particularly with regards to epithelial‑mesenchymal transition (EMT)‑associated migration and invasion of cancer cells. The purpose of the present study was to reveal the potential anticancer effects of polydatin on hepatocellular carcinoma (HCC) cells, particularly its effects on EMT. MTT assay was used to determine cell viability. Migration and invasion were evaluated through wound healing and transwell assays. Colony formation efficiency assay was conducted to detect proliferation. Flow cytometric analyses of apoptosis and cell cycle progression were performed following cells staining with Annexin V‑fluorescein isothiocyanate (FITC)/propidium iodide (PI) and PI alone, respectively. Western blotting was used to investigate relevant molecular mechanisms. The results indicated that polydatin inhibited proliferation via G2/M arrest, suppressed migration and invasion of HCC cells, and promoted their apoptosis. In addition, phosphorylated (p)‑protein kinase B (AKT), p‑Janus kinase 1 and p‑signal transducer and activator of transcription 3 (STAT3) levels were decreased as polydatin concentrations increased, and forkhead box protein O1 (FOXO1) expression was upregulated. Furthermore, the expression levels of various markers of EMT were reversed following treatment with polydatin. In conclusion, the present study validated that polydatin may inhibit proliferation via G2/M arrest, and suppressed EMT‑associated migration and invasion of HCC cells. The results also suggested that polydatin may promote HCC cell apoptosis by blocking the AKT/STAT3‑FOXO1 signaling pathway.
研究领域:
肿瘤学
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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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高影响因子
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