Cucurbitacin B attenuates LPS-induced skeletal muscle atrophy by inhibiting JAK2/STAT3 and suppressing proteasome activity

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Background Skeletal muscle atrophy results from an imbalance between protein synthesis and degradation, commonly driven by chronic inflammation. Cucurbitacin B (CuB), a natural tetracyclic triterpenoid with anti-inflammatory properties, has shown therapeutic promise in various inflammatory diseases, but its role in lipopolysaccharide (LPS)-induced muscle atrophy remains unexplored. Purpose This study aimed to evaluate the therapeutic efficacy of CuB against LPS-induced skeletal muscle atrophy and to elucidate its multi-target mechanisms. Methods Network pharmacology was used to predict the core targets and signaling pathways of CuB against inflammatory skeletal muscle atrophy. In vitro, the effects of CuB on myogenic differentiation, anabolic signaling, markers of protein degradation, JAK/STAT3 signaling, and inflammatory cytokine expression were evaluated by Western blotting, immunofluorescence, H&E staining, and ELISA. In vivo, an LPS-induced mouse model of inflammatory muscle atrophy was established via intraperitoneal injection. Muscle phenotype, molecular mechanisms, and motor function were comprehensively assessed to evaluate the therapeutic potential of CuB. Results Network pharmacology predicted that CuB targets key nodes including AKT1, STAT3, and Src, and modulates the PI3K-Akt, FoxO, and insulin signaling pathways. In vitro, CuB alleviated C2C12 myotube atrophy and enhanced anabolic signaling via the IGF-1R/Akt/mTOR axis, while downregulating FoxO3a-mediated atrophy-related genes and reducing global protein ubiquitination, as well as modulating autophagy-related markers. Notably, compared with the specific JAK2 inhibitor AG490, CuB exhibited broader anti-atrophic efficacy. In vivo, CuB significantly ameliorated LPS-induced losses in muscle mass, fiber structure, grip strength, and locomotor activity. Conclusion This study demonstrates that CuB alleviates LPS-induced skeletal muscle atrophy by promoting anabolic signaling and suppressing ubiquitin-proteasome pathway-related markers, while also modulating inflammatory responses.