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Research Paper|Volume 15, Issue 24|pp 15557—15577

Exploring the effect and mechanism of Aloin A against cancer cachexia-induced muscle atrophy via network pharmacology, molecular docking, molecular dynamics and experimental validation

Awaguli Dawuti1,3, Lisha Ma1, Xueyan An1, Jiawei Guan1, Changdong Zhou1, Linyun He1, Yue Xu4, Bo Han1, Abudumijiti Abulizi1,2
  • 1Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, College of Pharmacy, Shihezi University, Shihezi 832002, China
  • 2State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
  • 3State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
  • 4Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
* Equal contribution
Received: August 21, 2023Accepted: November 6, 2023Published: December 29, 2023
https://doi.org/10.18632/aging.205416

Copyright: © 2023 Dawuti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

80% of advanced cancer patients suffer from cachexia, but there are no FDA-approved drugs. Therefore, it is imperative to discover potential drugs.

Objective: This study aims at exploring the effect and targets of Aloin A against cancer cachexia (CC)-induced muscle atrophy.

Methods: Network pharmacology, molecular docking, molecular dynamics (MD) and animal model of CC-induced muscle atrophy with a series of behavior tests, muscle quality, HE staining and RT-PCR were performed to investigate the anticachectic effects and targets of Aloin A and its molecular mechanism.

Results: Based on network pharmacology, 51 potential targets of Aloin A on CC-induced muscle atrophy were found, and then 10 hub genes were predicted by the PPI network. Next, KEGG and GO enrichment analysis showed that the anticachectic effect of Aloin A is associated with PI3K-AKT, MAPK, TNF, TLR, etc., pathways, and biological processes like inflammation, apoptosis and cell proliferation. Molecular docking and MD results showed good binding ability between the Aloin A and key targets. Moreover, experiments in vivo demonstrated that Aloin A effectively rescued muscle function and wasting by improving muscle quality, mean CSA, and distribution of muscle fibers by regulating HSP90AA1/AKT signaling in tumor-bearing mice.

Conclusion: This study offers new insights for researchers to understand the effect and mechanism of Aloin A against CC using network pharmacology, molecular docking, MD and experimental validation, and Aloin A retards CC-induced muscle wasting through multiple targets and pathways, including HSP90AA1/AKT signaling, which provides evidence for Aloin A as a potential therapy for cancer cachexia in clinic.