Loss of LCN2 Function Ameliorates Glucocorticoid‐Induced Muscle Atrophy via Remodeling the Extracellular Matrix

Chronic glucocorticoid (GC) exposure is the leading clinical cause of skeletal muscle atrophy, steroid myopathy, and secondary sarcopenia, triggering irreversible motor function decline, disease progression, and elevated all-cause mortality. The underlying pathological mechanisms remain unclear, and no safe and effective targeted interventions are currently available. This study identifies Lipocalin 2 (LCN2) as a pivotal driver of GC-induced muscle atrophy. Using multi-omics analysis, dexamethasone-induced mouse models, primary myotube models, and gain/loss-of-function assays, we found that LCN2 was the most strikingly upregulated factor in atrophic muscle, and that its transcription was directly activated by glucocorticoid receptor (GR) binding to the conserved glucocorticoid response element (GRE) in its promoter. Muscle-specific LCN2 overexpression disrupts extracellular matrix (ECM) homeostasis and triggers severe muscle atrophy and motor dysfunction, whereas LCN2 silencing markedly alleviates GC-induced ECM injury and atrophy without impairing normal muscle homeostasis. Mechanistically, the interaction of LCN2 with matrix metalloproteinase 9 (MMP9) triggers ECM dysregulation and consequent focal adhesion kinase (FAK) signaling inactivation, which represses the PI3K-Akt-mTOR anabolic cascade and activates FoxO-driven catabolic signaling, thereby leading to dysregulated muscle protein metabolism. This study reveals the core pathogenic role of the LCN2-MMP9-ECM-FAK axis in GC-induced muscle atrophy, providing a promising novel therapeutic target for steroid myopathy.