The GPCR-like transmembrane protein Smoothened (Smo) is an indispensable transducer in Hedgehog (Hh) pathway， its hyperactivation leads to several human cancers， including non-small cell lung cancer (NSCLC). The mechanism governing Smo stability still remains elusive. Here， we perform a modifier screening in Drosophila， and find that the E3 ligase dHerc4 degrades dSmo. Depletion of dherc4 increases dSmo protein and activates Hh pathway. In addition， we reveal that HERC4 is downregulated in NSCLC samples， negative correlating with Smo. HERC4 interacts with Smo reciprocally in NSCLC cells. Finally， we show that knockdown of herc4 activates Hh pathway and promotes NSCLC cell proliferation. Taken together， our studies have demonstrated that HERC4 acts as a tumor suppressor via destabilizing the oncoprotein Smo， and provided HERC4 as a promising therapeutic target for NSCLC treatment.