The Sonic hedgehog (Shh) signaling pathway is an essential pathway in the human body that plays an important role in embryogenesis and tissue homeostasis. Aberrant activation of this pathway has been linked to the development of different diseases, ranging from
cancer to immune dysregulation and
infections.Uncontrolled activation of the pathway through sporadic mutations or other mechanisms is associated with
cancer development and progression in various
malignancies, such as
basal cell carcinoma,
medulloblastoma,
pancreatic cancer,
breast cancer and
small-cell lung carcinoma. Targeted inhibition of the pathway components has therefore emerged as an attractive and validated therapeutic strategy for the treatment of a wide range of
cancers. Currently, two main components of the pathway, the
smoothened receptor and the
glioma-associated oncogene homolog transcriptional factors, have been investigated for the development of targeted drugs, leading to the marketing authorization of three
smoothened receptor inhibitors for the treatment of
basal cell carcinoma and
acute myeloid leukemia.The Shh pathway also seems to be involved in regulating the immune response, possibly playing a role in immune system evasions by
tumors, development of
autoimmune diseases, such as
rheumatoid arthritis and
Crohn's disease, airway
inflammation, and diseases related to aberrant activation of T-helper 2 cellular response, such as
allergy,
atopic dermatitis, and
asthma.Finally, the Shh pathway is involved in pathogen-mediated
infection, including
influenza-A and, more recently, SARS-CoV-2 viruses. Therefore, agents that inhibit the Shh signaling pathway might be used to treat pathogenic
infections, shifting the therapeutic approach from strain-specific treatments to host-based strategies that target highly conserved host targets.