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

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.