Hedgehog signaling pathway components (Hh pathway)

The Hedgehog (Hh) signaling pathway is a fundamental regulator of embryonic development, governing processes such as tissue patterning, cell differentiation, and organogenesis [2, 4]. In adults, the pathway remains active in specific tissues to maintain stem cell populations and facilitate tissue repair and regeneration [2, 15]. The canonical pathway involves the binding of Hedgehog ligands (Sonic, Indian, or Desert) to the Patched-1 (PTCH1) receptor, which subsequently releases the inhibition of the Smoothened (SMO) protein [1, 11]. Activated SMO triggers a downstream signaling cascade that results in the nuclear translocation of GLI transcription factors, which drive the expression of genes associated with cell cycle progression and survival [1, 14]. Aberrant activation of Hedgehog signaling, frequently caused by loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO, is a well-established driver of various cancers, including basal cell carcinoma and medulloblastoma [5, 11]. Therapeutic intervention has primarily focused on SMO inhibitors like vismodegib and sonidegib, which are FDA-approved for the treatment of advanced basal cell carcinoma [1, 8]. Despite their efficacy, these drugs are associated with significant on-target side effects, most notably severe teratogenicity, which necessitates strict pregnancy prevention measures [3, 20]. Additionally, the development of resistance through secondary mutations in SMO or activation of non-canonical bypass pathways presents a major challenge in long-term clinical management [10, 16].

Other names

Hedgehog signaling pathwayHh signaling pathwayHedgehog-Patched-Smoothened pathwayHh-Gli pathway

Inhibition of Smoothened (SMO) protein activity to prevent the activation and nuclear translocation of GLI transcription factors, or direct inhibition of GLI proteins, thereby suppressing the expression of genes involved in cell proliferation and survival [1, 10, 17].