FoxO1 as a Hub in Immunosenescence Induced by Hepatocellular Carcinoma and the Effect of Yangyin Fuzheng Jiedu Prescription.

IF 5.1 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2025-03-05 eCollection Date: 2025-01-01 DOI:10.2147/DDDT.S492576

Yuqing Xie, Fengna Yan, Xiaoli Liu, Lihua Yu, Huiwen Yan, Zimeng Shang, Yaxian Kong, Zhiyun Yang

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Abstract

Purpose: Yangyin Fuzheng Jiedu Prescription (YFJP) is a traditional Chinese medicine (TCM) used for the treatment of hepatocellular carcinoma (HCC). However, the potential mechanisms remain unclear. The objective of this study is to clarify the mechanism of action of YFJP in treating HCC.

Methods: By constructing networks, the active components and molecular targets of YFJP in the treatment of HCC were explored. The TCGA database was utilized to analyze the correlation between the core target and the overall survival (OS) of patients with HCC. The regulatory effect of YFJP on T cell was evaluated by detecting samples from patients with HCC. The molecular mechanism of YFJP in treating HCC was validated through in vivo and in vitro experiments.

Results: Constructing networks and analyse indicated that the key targets of YFJP in the treatment of HCC is FoxO1. Analysis of the HCC patient cohort in the TCGA database demonstrated that FoxO1 is an independent protective factor for overall survival in patients with HCC. Pathway enrichment analysis enriched FoxO signaling pathway and Cellular senescence pathway. Prospectively collecting samples from patients with HCC suggested that YFJP treatment increased the proportion of CD8⁺ T cells. In vivo experiments showed that YFJP treatment ameliorated CD8⁺ T cell senescence in tumor-bearing mice. Western blot, flow cytometry and multi-color immunofluorescence co-staining showed that YFJP treatment increased the expression of FoxO1 in CD8⁺ T cells. The primary CD8⁺ T cells were sorted and co-cultured with an HCC cell line in vitro. Inhibiting the expression of FoxO1 in CD8⁺T cells confirmed that FoxO1 is a key target for YFJP to improve the senescence of CD8⁺ T cell.

Conclusion: FoxO1 is the key molecular target of YFJP in improving CD8⁺ T cell senescence in HCC. This study preliminarily clarified the mechanism of YFJP in regulating immunosenescence of HCC.

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fox01在肝癌免疫衰老中的作用及养阴扶正解毒方的作用。

目的：养阴扶正解毒方（YFJP）是治疗肝细胞癌的中药。然而，潜在的机制仍不清楚。本研究的目的是阐明YFJP治疗HCC的作用机制。方法：通过构建网络，探索YFJP治疗HCC的有效成分和分子靶点。利用TCGA数据库分析核心靶点与HCC患者总生存期（OS）的相关性。通过检测肝癌患者样本来评估YFJP对T细胞的调节作用。通过体内和体外实验验证了YFJP治疗HCC的分子机制。结果：构建网络和分析表明，YFJP治疗HCC的关键靶点是fox01。TCGA数据库中HCC患者队列的分析表明，fox01是HCC患者总生存的独立保护因子。通路富集分析富集了FoxO信号通路和细胞衰老通路。从HCC患者中前瞻性收集样本表明，YFJP治疗增加了CD8+ T细胞的比例。体内实验表明，YFJP治疗可改善荷瘤小鼠CD8+ T细胞衰老。Western blot、流式细胞术和多色免疫荧光共染色结果显示，YFJP处理可提高CD8+ T细胞中FoxO1的表达。将原代CD8+ T细胞分选后与肝癌细胞系体外共培养。抑制CD8+T细胞中FoxO1的表达，证实FoxO1是YFJP改善CD8+T细胞衰老的关键靶点。结论：FoxO1是YFJP改善HCC中CD8+ T细胞衰老的关键分子靶点。本研究初步阐明了YFJP调节肝癌细胞免疫衰老的机制。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.