Systems Pharmacology-based Drug Discovery and Active Mechanism of Ganoderma lucidum Triterpenoids for Type 2 Diabetes Mellitus by Integrating Network Pharmacology and Molecular Docking
Authors: Shi Junkai , Chen Jialiang , Cheng Chitong , Li Wei , Li Ming , Ye Shuhong , Liu Zhaofang , Ding Yan 
Published: February 2025

Background:
Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disease primarily characterized
by insufficient insulin secretion or reduced insulin sensitivity in the body's cells, leading to persistently
high blood glucose levels. Ganoderma lucidum triterpenoids, as important secondary metabolites of
Ganoderma lucidum, have shown preliminary potential efficacy in the treatment of T2DM according to existing
research. However, due to the structural complexity and diversity of these triterpenoid compounds, as well
as the intricate interactions between their therapeutic targets and active ingredients, the precise molecular and
pharmacological mechanisms remain to be further explored.

Objective:
In the present research, we aim to fully employ the integrated approach of network pharmacology
and molecular docking methodologies, delving deeply into the potential therapeutic targets and their underlying
pharmacological mechanisms in the management of T2DM via Ganoderma lucidum triterpenoids.

Methods:
The active compounds were sourced from prior research and the Traditional Chinese Medicine Systems
Pharmacology (TCMSP) database. Their potential targets were predicted with the aid of Swiss Target
Prediction. Genes linked to T2DM were gathered from DisGeNET and GeneCards. Using Cytoscape, we established
the network connecting active ingredients, targets, and pathways, and the target protein-protein interaction
(PPI) network was created using data from the STRING database. The core targets of Ganoderma
lucidum triterpenoids underwent gene enrichment analysis via DAVID. Lastly, to validate our chosen
Ganoderma lucidum triterpenoids, we conducted molecular docking experiments between the compounds and
their targets.

Results:
A total of 53 Ganoderma lucidum triterpenoids and 116 associated targets were identified. Among
these, SRC, MAPK1, MAPK3, HSP90AA1, TP53, PIK3CA, and AKT1 emerged as pivotal targets. We retrieved
447 Gene Ontology (GO) functional annotations and 153 Kyoto Encyclopedia of Genes and Genomes
(KEGG) pathways, notably including the PI3K-Akt signaling pathway, Endocrine resistance, Rap1 signaling
pathway, and Lipid and Atherosclerosis, which are known to be associated with T2DM. Our findings suggest
that Ganoderma lucidum triterpenoids may confer resistance to T2DM through mechanisms related to hyperexcitability,
cell death, cell survival, proliferation, differentiation, and inflammation.

result:
In total, 53 Ganoderma lucidum triterpenoids and 116 associated targets were yielded. SRC, MAPK1, MAPK3, HSP90AA1, TP53, PIK3CA, and AKT1 were defined as core targets. 447 GO function items and 153 KEGG pathways were obtained, including PI3K-Akt signaling pathway, Endocrine resistance, Rap1 signaling pathway, and Lipid and Atherosclerosis that were related to T2DM. Ganoderma lucidum triterpenoids could enable resistance against T2DM by hyperexcitability, cell death, cell survival, proliferation, differentiation, and inflammation.

Conclusion:
A comprehensive, interdisciplinary, and multi-technology approach has been established, which
uncovers the collaborative effects and underlying principles of Ganoderma lucidum triterpenoids in the management
and therapy of T2DM from a holistic perspective. This approach provides new insights into the development
of novel biological control products for Type 2 Diabetes Mellitus (T2DM) and lays the foundation
for future systematic studies on the interactions between Ganoderma triterpenes and different targets, elucidating
their primary and secondary pathways for lowering blood glucose.