Glucocorticoids (GCs) are frequently used to treat chronic disorders in children， including inflammation and cancer. Prolonged treatment with GCs is well known to impair bone growth， an effect linked to increased apoptosis and suppressed proliferation in growth plate chondrocytes. We hypothesized that the endogenous antiapoptotic protein humanin (HN) may prevent these effects. Interestingly， GC-induced bone growth impairment and chondrocyte apoptosis was prevented in HN overexpressing mice， HN-treated wild-type mice， and in HN-treated cultured rat metatarsal bones. GC-induced suppression of chondrocyte proliferation was also prevented by HN. Furthermore， GC treatment reduced Indian Hedgehog expression in growth plates of wild-type mice but not in HN overexpressing mice or HN-treated wild-type animals. A Hedgehog (Hh) antagonist， vismodegib， was found to suppress the growth of cultured rat metatarsal bones， and this effect was also prevented by HN. Importantly， HN did not interfere with the desired anti-inflammatory effects of GCs. We conclude that HN is a novel regulator of Hh signaling preventing GC-induced bone growth impairment without interfering with desired effects of GCs. Our data may open for clinical studies exploring a new possible strategy to prevent GC-induced bone growth impairment by cotreating with HN.-Zaman， F.， Zhao， Y.， Celvin， B.， Mehta， H. H.， Wan， J.， Chrysis， D.， Ohlsson， C.， Fadeel， B.， Cohen， P.， Sävendahl， L. Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid-induced bone growth impairment.