Phillyrin attenuates dexamethasone-induced skeletal muscle atrophy by inhibiting 15-PGDH

Glucocorticoid-induced skeletal muscle atrophy is characterized by progressive loss of muscle mass and function, yet effective pharmacological interventions remain limited. Prostaglandin E₂ (PGE₂) plays an important role in maintaining muscle regeneration, and its degradation is primarily controlled by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Here we investigated whether phillyrin, a natural lignan compound, protects against dexamethasone (DEX)-induced muscle atrophy in mice. Phillyrin treatment significantly attenuated DEX-induced reductions in muscle mass and improved grip strength and motor endurance. Histological analysis showed that phillyrin alleviated myofiber atrophy and preserved mitochondrial ultrastructure. Mechanistically, phillyrin suppressed the upregulation of 15-PGDH and restored intramuscular PGE₂ levels, accompanied by recovery of EP4 signaling. These changes were associated with inhibition of FOXO3a-mediated proteolysis and partial restoration of mTOR and PGC-1α signaling in skeletal muscle. Collectively, these findings indicate that phillyrin protects against glucocorticoid-induced muscle atrophy, potentially through modulation of the 15-PGDH/PGE₂ pathway. These findings suggest that phillyrin may represent a potential therapeutic candidate for the treatment of glucocorticoid-induced skeletal muscle atrophy.