PHARMACOLOGICAL RESEARCH
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2025
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IF 10.5
Yuanyuan Tang,Han Wu,Ping Yan,Zhangxuan Yue,Zeyu Hu,Xunqi Liao,Yali Wang,Ye Lin,Liqing Li,Xiong Cai
Rheumatoid arthritis (RA) is a challenging autoimmune disorder characterized by fibroblast-like synoviocyte (FLS)-driven synovitis and joint destruction. Halofuginone (HF), a bioactive derivative of febrifugine isolated from the root of Dichroa febrifuga Lour., exhibits therapeutic potential in RA yet its molecular targets remain to be elucidated. In this study, we demonstrated that oral HF treatment (1.25 and 2.5 mg/kg, every other day) significantly inhibited disease progression of adjuvant-induced arthritis (AIA) in rats manifested by markedly less extent of synovial proliferation, cartilage destruction, and bone erosion. HF (0.1–0.8 μM) exerted dose-dependent inhibition on RA-FLS proliferation, invasion, and inflammatory response via targeting HSPA8 as confirmed by surface plasmon resonance (SPR) analysis showing direct binding (KD=3.877 μM). Notably, HSPA8 exhibited pronounced overexpression in AIA synovial tissue and RA-FLS versus controls. siRNA knockdown of HSPA8 significantly reduced RA-FLS proliferation, invasion, and inflammatory response, while adenoviral overexpression of HSPA8 exacerbated these phenotypes. Mechanistically, HF markedly reduced HSPA8 expression in the synovium of AIA rats and RA-FLS. These findings establish HSPA8 as a novel therapeutic target in RA and validate HF as its natural inhibitor, providing mechanistic insights for HSPA8-targeted RA therapies.
研究领域:
免疫学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
POULTRY SCIENCE
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2025
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IF 4.2
Di Sun,Wenze Cheng,Zheng Li,Hui Yao,Mafeng Liu,Mingshu Wang,Shun Chen,Yukun Zhu,Jingming Wang,Yuan Deng,Funeng Xu,Xumin Ou,Renyong Jia,Dekang Zhu,Xinxin Zhao,Qiao Yang,Ying Wu,Shaqiu Zhang,Juan Huang,Bin Tian,Yu He,Zhen Wu,Anchun Cheng
Duck hepatitis A virus type 3 (DHAV-3) has emerged as a dominant pathogen responsible for duck viral hepatitis, leading to significant economic losses in the duck industry. Given that current control strategies, primarily reliant on vaccination, often face limitations, this study investigates a host-directed therapeutic (HDT) strategy focused on targeting host factors essential for DHAV-3 replication. We identified the heat shock protein family A member 8 (HSPA8) as a key interactor of the viral structural protein VP0 through GST pull-down and mass spectrometry. Functional assays confirmed that HSPA8 significantly promotes DHAV-3 replication; its overexpression enhanced viral yield, while its inhibition suppressed it. Building on these findings, we explored oxymatrine (OMT), a natural compound derived from Sophora flavescens (Kushen), and found that it effectively downregulates HSPA8 expression, thereby inhibiting viral replication in vitro . In a duckling model, OMT treatment provided significant protection, dose-dependently improving survival rates, reducing viral loads, and alleviating DHAV-3-induced liver injury and apoptosis. Transcriptomic profiling revealed that OMT mitigates liver damage through dual mechanisms: by suppressing the overactivated RIG-I-like receptor signaling pathway and inhibiting the apoptosis pathway. Our work establishes HSPA8 as a promising pan-picornaviral target and identifies OMT as a novel and effective HDT candidate against DHAV-3 infection.
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Xiaoke Wu,Yugang Xiao,Zhirui Song,Hongbo Zhang,Li Yin,Nannan Fang,Qubo Zhu
HSPA8 is first identified as a new PROTAC target for targeted protein degradation in HCC. • HCR-assembled multivalent DNA nanocentipede LC-42 overcomes the hook effect with sustained degradation. • LC-42 improves targeting, cellular uptake, stability, and PROTAC efficiency; the platform is modular and extensible. Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide. However, the clinical translation of proteolysis-targeting chimeras (PROTACs) for HCC therapy remains restricted by the hook effect, limited tumor selectivity, and inefficient intracellular delivery. Herein, we developed a modular hybridization chain reaction (HCR)-programmable multivalent nucleic acid PROTAC platform and demonstrated, for the first time, that heat shock protein A8 (HSPA8) can serve as a target for targeted protein degradation in HCC. Using the HSPA8-binding DNA aptamer AS42 as the molecular recognition module, we constructed a monovalent aptamer-PROTAC (AS-42) and a multivalent DNA nanocentipede-based aptamer-PROTAC (LC-42) through enzyme-free HCR self-assembly. Owing to its programmable multivalent architecture, LC-42 efficiently induced HSPA8 degradation in HepG2 cells at 20 nM and maintained comparable activity at 200 nM, effectively overcoming the hook effect while exhibiting significantly enhanced degradation efficiency compared with AS-42. LC-42 further exhibited superior antiproliferative and pro-apoptotic activities in vitro, along with enhanced tumor accumulation and remarkable tumor growth inhibition in HepG2 xenograft models with favorable systemic biocompatibility. Furthermore, replacing AS-42 with an epidermal growth factor receptor (EGFR)-binding aptamer readily generated an EGFR-targeted degrader while preserving efficient degradation, providing proof-of-concept for the modularity and extensibility of this platform. Collectively, this work establishes HSPA8 as a previously unrecognized target for targeted protein degradation and introduces a modular, programmable DNA nanoplatform for engineering next-generation multivalent nucleic acid PROTACs. This platform thus provides a versatile strategy for precision targeted protein degradation in cancer therapy. Download: Download high-res image (153KB) Download: Download full-size image
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DOI
高影响因子
MICROCHEMICAL JOURNAL
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2025
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IF 5.1
Yinglei Liu,Guojie Hao,Miaomiao Ma,Haolong Wang,Yu Sun,Wenqiang Zhang,Xingpeng Kang,Haofeng Song,Yilin Lu,Junfang Wu,Wenqiang Fan,Yanli Liu,Juntang Lin
This study aims to systematically characterize the protein and metabolite compositions of the secretome isolated from menstrual blood-derived endometrial stem cell (MenSC-S), elucidate its biological properties, explore potential active components and mechanisms of action as an acellular therapeutic agent, and provide a scientific foundation for advancing its clinical applications. A total of 878 shared proteins were identified in MenSC-S samples from volunteers of varying ages (25, 35, and 45 years), among which 242 were recognized as secretory proteins. The investigation revealed that the key protein heat shock protein family A member 8 (HSPA8) negatively regulates the assembly of the NLRP3 inflammasome complex by activating the PI3K-Akt signaling pathway. Untargeted metabolomic analysis indicated that metabolites present in MenSC-S play significant roles in biological processes such as nitrogen metabolism, amino acid synthesis, and detoxification. Integrated protein-metabolite analysis highlighted the considerable complexity of both proteome and metabolome along with their synergistic effects. Dialysis experiments confirmed that the metabolite fractions within MenSC-S are crucial for enhancing cell viability in both normal cells and those damaged by Cisplatin. This study partially elucidates the biological properties of MenSC-S along with potential molecular mechanisms underlying its therapeutic effects. It not only identifies specific potential active components for developing acellular therapeutic strategies targeting various diseases based on MenSC-S but also establishes a foundation for further exploration into the clinical translation of mesenchymal stem cells (MSCs) and their derivatives.
研究领域:
干细胞生物学
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再生医学
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分子生物学
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免疫调节
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代谢组学
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药理学
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转化医学
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DOI
高影响因子
Frontiers in Pharmacology
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2023
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IF 5.6
Cao Xu,Zhang Ningyi,Chen Hening,Wang Wei,Liang Yijun,Zhang Jiaxin,Liu Ruijia,Li Shuo,Yao Yuhao,Jin Qian,Guo Ziwei,Chen Yue,Gong Yuanyuan,Li Xiaoke,Zao Xiaobin,Ye Yong’an
The JiGuCao capsule formula (JCF) has demonstrated promising curative effects in treating chronic hepatitis B (CHB) in clinical trials. Here, we aimed to investigate JCF’s function and mechanism in diseases related to the hepatitis B virus (HBV). We used mass spectrometry (MS) to identify the active metabolites of JCF and established the HBV replication mouse model by hydrodynamically injecting HBV replication plasmids into the mice’s tail vein. Liposomes were used to transfect the plasmids into the cells. The CCK-8 kit identified cell viability. We detected the levels of HBV s antigen (HBsAg) and HBV e antigen (HBeAg) by the quantitative determination kits. qRT-PCR and Western blot were used to detect the genes’ expression. The key pathways and key genes related to JCF on CHB treatment were obtained by network pharmacological analysis. Our results showed that JCF accelerated the elimination of HBsAg in mice. JCF and its medicated serum inhibited HBV replication and proliferation of HBV-replicating hepatoma cells in vitro. And the key targets of JCF in treating CHB were CASP3, CXCL8, EGFR, HSPA8, IL6, MDM2, MMP9, NR3C1, PTGS2, and VEGFA. Furthermore, these key targets were related to pathways in cancer, hepatitis B, microRNAs in cancer, PI3K-Akt signaling, and proteoglycans in cancer pathways. Finally, Cholic Acid, Deoxycholic Acid, and 3′, 4′, 7-Trihydroxyflavone were the main active metabolites of JCF that we obtained. JCF employed its active metabolites to perform an anti-HBV effect and prevent the development of HBV-related diseases.
研究领域:
药理学
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病毒学
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分子生物学
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网络药理学
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肝病学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）