Gooseberry, citrus peel, and licorice extracts as multi-target modulators of inflammatory and metabolic pathways in LPS-induced muscle wasting: integrative network pharmacology and computational docking analysis
TL;DR
Gooseberry, licorice, and citrus peel extracts exhibit multi-pathway muscle-protective effects through coordinated modulation of oxidative stress, inflammation, and TGF-β signaling, suggesting that the ADAMTSL3 rs4842838 variant disrupted TGF-β signaling and contributed to muscle wasting through dysregulated inflammatory responses.
Abstract
Sarcopenia affects over 50 million individuals worldwide but lacks precision therapeutic strategies. The ADAMTSL3 rs4842838 (Val661Leu) variant may dysregulate TGF-β signaling and inflammatory responses in muscle wasting. This study aimed to establish an integrated computational-to-biological framework for identifying natural compounds (NCs) targeting inflammatory muscle wasting, using ADAMTSL3 rs4842838 (Val661Leu) variant-informed molecular docking and network pharmacology to prioritize candidate herbal extracts, which were subsequently validated in lipopolysaccharide (LPS)-induced C2C12 myotubes. Molecular docking of 25,000 NCs was performed against wild-type (WT) and mutant-type (MT) ADAMTSL3 Val661Leu structures. Compounds with binding energies ≤–9.5 kcal/mol were evaluated via network pharmacology. Biological validation used LPS-induced inflammatory muscle wasting in C2C12 myoblasts treated with gooseberry, licorice, and citrus peel extracts (1–125 µg/mL). Molecular clustering revealed superior performance for MT-selected NCs versus WT (silhouette score 0.75 vs. 0.63). MT-selected NCs required nitrogen-containing groups. Network pharmacology analysis identified licorice NCs targeting PDGFRB, AKT1, mTOR, and SOD1 pathways, while gooseberry NCs modulated matrix regulation via MMP3/MMP9. LPS treatment increased MMP3 expression by 51%; gooseberry and licorice extracts normalized MMP3 levels, while citrus peel extract showed partial recovery. All extracts upregulated muscle development genes (MYOG, MyoD1, ADAMTSL3), downregulated myostatin, reduced lipid peroxidation, and suppressed inflammatory markers (IL-1β, IL-6) (P < 0.05). The extracts enhanced TGF-β and insulin signaling while attenuating NF-κB activation, suggesting that the ADAMTSL3 rs4842838 variant disrupted TGF-β signaling and contributed to muscle wasting through dysregulated inflammatory responses. In conclusion, docking-informed network pharmacology analysis combined with in vitro validation supports a precision nutrition framework for inflammatory muscle wasting. Gooseberry, licorice, and citrus peel extracts exhibit multi-pathway muscle-protective effects through coordinated modulation of oxidative stress, inflammation, and TGF-β signaling.