Network pharmacology and experimental validation reveal that betulin alleviates 5-fluorouracil-induced intestinal injury by inhibiting intestinal senescence and enhances antitumor efficacy

文献类型： 外文期刊

第一作者： Wang, Zhi-wei

作者： Wang, Zhi-wei;Dai, Qian-long;Liu, Zhen-lin;Lian, Wei;Zhao, Yue;Wang, Xiao-bo;Wu, Xiao-jian;Zhao, Cheng-gang;Li, Li-hua

作者机构：

关键词： Betulin; Cellular senescence; 5-Fluorouracil; Intestinal damage; Network; pharmacology

期刊名称：JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS （ 影响因子：3.8； 五年影响因子：3.5 ）

ISSN： 0022-3565

年卷期： 2025 年 392 卷 9 期

页码：

收录情况： SCI

摘要： 5-Fluorouracil (5-FU) remains the first-line chemotherapeutic agent for colorectal cancer. Although 5-FU significantly improves patient survival, its severe gastrointestinal toxicity & horbar;particularly intestinal injury and diarrhea & horbar;impairs treatment adherence and patient quality of life, often leading to therapeutic failure. Thus, effective interventions to prevent or mitigate these adverse effects are urgently needed. Betulin (BET), a natural pentacyclic triterpenoid derived primarily from birch bark, exhibits various biological activities, including anti-inflammatory, antioxidant, antiviral, and antitumor effects. Its anti-inflammatory and antioxidant properties suggest betulin (BET) as a promising candidate for alleviating chemotherapy-induced tissue damage. However, its impact on 5-FU-induced intestinal injury remains unclear. The findings of this study revealed that 5-FU led to significant intestinal injury by promoting cellular senescence and exacerbating the inflammatory response. BET mitigates these effects by decreasing senescence-associated ss-galactosidase activity and downregulating key senescence markers such as p53, p21, and p16. Moreover, BET modulates senescence-associated secretory phenotype factors, thereby reversing the proinflammatory microenvironment elicited by 5-FU. Integrating network pharmacology, Mendelian randomization, and experimental validation, we identified the mechanistic target of rapamycin/mitogen-activated protein kinase signaling pathway as a pivotal mediator of BET's protective effects against 5-FU-induced intestinal injury. In conclusion, our study reveals that 5-FU-induced intestinal damage is driven by cellular senescence, which BET effectively ameliorates through suppression of senescence and inflammation. These findings provide a novel framework for targeting antisenescence strategies to alleviate chemotherapy-associated intestinal toxicity. Significance Statement: This study identifies betulin as a novel agent that alleviates 5-fluorouracil-induced intestinal injury by inhibiting cellular senescence and inflammation via the mechanistic target of rapamycin/mitogen-activated protein kinase pathways. These findings highlight antisenescence as a promising therapeutic strategy to mitigate chemotherapy-induced gastrointestinal toxicity. (c) 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

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