Network Pharmacology and Experimental Validation Reveal Ganodermanontriol Modulates Pneumonia via <scp>TNF</scp> / <scp>NF</scp> ‐ <scp>κB</scp> / <scp>MAPKs</scp> Signaling Pathway

<i>Ganoderma lucidum</i> (Leyss. ex Fr.) Karst, commonly known as Lingzhi, has long been employed in traditional Chinese medicine for its medicinal properties, particularly in alleviating respiratory issues like cough and asthma. Recognized both as a therapeutic agent and an edible supplement, Lingzhi is celebrated for its health-promoting benefits. Despite its widespread use, the effectiveness of <i>G. lucidum</i> in treating pneumonia has not been extensively studied, highlighting the need for further research. This research aimed to evaluate the potential of <i>G. lucidum</i> in pneumonia treatment and to uncover the mechanisms behind its effects, specifically examining how its active constituents influence inflammatory pathways. The study utilized approaches such as network pharmacology, bioinformatics, molecular docking, and in vivo experiments. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) analyses revealed eight triterpenoids in <i>G. lucidum</i>, with ganodermanontriol being the most prominent. Molecular docking studies anticipated the interactions between these compounds and target proteins, while in vivo experiments on pneumonia-induced rat models assessed the efficacy of ganodermanontriol. Additionally, HPLC and LC-MS confirmed the presence of eight triterpenoids in the ethanol extract of <i>G. lucidum</i>, predominantly ganodermanontriol. Network pharmacology and molecular docking identified key genes-including TNF, EGFR, ESR1, HIF1A, HSP90AA1, and SRC-that played significant roles in the regulation of inflammatory pathways. In vivo results demonstrated that ganodermanontriol treatment mitigated lung tissue damage in rats with experimentally induced pneumonia by reducing the release of inflammatory mediators. Further mechanistic studies showed that ganodermanontriol downregulated TNF-α and inhibited the NF-κB/MAPKs signaling pathways. These findings suggested that ganodermanontriol holds promising potential as an anti-inflammatory agent for pneumonia by targeting the TNF/NF-κB/MAPKs signaling pathway, offering a novel therapeutic approach.