Knockdown of CLEC4D alleviates myoblast dysfunction and inflammation in sarcopenia by inhibiting the JAK/STAT pathway.

OBJECTIVE: Sarcopenia is a progressive skeletal muscle disease that is prevalent among the elderly. We aim to explore the role of the C-type lectin domain containing 4, member D (CLEC4D) in sarcopenia. METHODS: Hub genes were identified from protein-protein interaction networks based on differentially expressed genes from GSE145480 and GSE139204 datasets. Sarcopenia in mice was induced by Dexamethasone. Pathological estimation was conducted using hematoxylin-eosin and Masson staining. Myoblasts were treated with D-galactose (D-gal) to induce senescence, which was assessed by senescence-associated β-galactosidase staining. The viability and apoptosis were evaluated using the Cell Counting Kit-8 assay and flow cytometry. Protein and gene expression were examined by western blot and real-time quantitative polymerase chain reaction. Enzyme-linked immunosorbent assays were performed to measure inflammatory factors. RESULTS: We identified 8 hub genes associated with sarcopenia, among which CCL5, CLEC4D, LGALS3, ESR2, FCGR4, and CLEC4N were upregulated in sarcopenia. CLEC4D knockdown enhanced myogenic differentiation, suppressed muscular fibrosis and atrophy, and alleviated sarcopenia in mice via reducing inflammatory cytokine levels. CLEC4D knockdown attenuated D-gal-induced myoblast dysfunction by enhancing differentiation and downregulating the expression of inflammatory cytokines and muscle atrophy markers. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway was activated in D-gal-induced myoblasts. CLEC4D knockdown inhibited the JAK/STAT pathway in D-gal-induced myoblasts. Notably, an activator of the JAK/STAT pathway reversed the inhibitory effect of CLEC4D knockdown on D-gal-induced myoblast dysfunction and inflammation. CONCLUSION: Targeting CLEC4D represents a promising therapeutic strategy for sarcopenia, as its knockdown suppresses disease progression by inhibiting the JAK/STAT signaling pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12891-025-09085-x.