The hedgehog (HH) gene was first discovered in Drosophila for its role in embryonic development,however, it plays a crucial and conserved role in numerous processes of vertebrates, such as embryogenesis, epithelial-mesenchymal transition, and cellular development (1-3). Secreted HH ligands can diffuse through the extracellular matrix to act on distant cells (4). In this regard, three homologous ligands for HH have been identified in mammals, including desert (DHH), sonic (SHH), and Indian (IHH) HH ligands (5, 6). The interaction of the SHH ligand with the Patched receptor (PTCH1) on recipient cells activates the smoothen (SMO) by relieving its suppression and subsequently activates transcription factors in the glioma-associated oncogene family (7). Recent findings have suggested that there is an interaction between the SHH pathway and other signaling pathways, including Wnt/β-catenin, transforming growth factor β, mammalian target of rapamycin, and notch (8). Evidence implies that the disruption of HH signaling is effectively involved in developing cancers in various organs (9). In this regard, recent studies have revealed that patients with mutations resulting in the impaired activity of SHH signaling effectors Patched and SMO may develop basalcell carcinomas (10). On the other hand, an impairment in the pathway has been found to cause various metabolic disorders. It has been suggested that impairments in the HH signaling pathways may contribute to several lipid/ lysosomal storage disorder diseases, such as NiemannPick C 1 and 2 (NPC1, 2) and mucopolysaccharidosis type II (Hunter disease) (10, 11)

Hedgehog signalling pathway has not only a critical role in cell proliferation, differentiation and tissue polarity at embryonic period but also has a vital role in stem cell proliferation, tissue healing and carcinogenesis. Recent research has increased our understanding of this pathway and its relation to other signaling pathways. In addition, a large number of studies confirmed the alteration of Hh signalling pathway in various types of human malignancies including basal cell carcinomas, medulloblastomas, lung, gastrointestinal, ovarian, breast, prostate cancers and leukemia. More than 50 small biomolecules have been introduced which have inhibitory effects on Hh signalling pathway. Although, in many tumors some acceptable results have been showed in phase I clinical trial, closer studies are required to improve drug bioavailability, to decrease the side effects and to find the right small molecules for specific types of cancers, considering patients overall benefits as well.