Hedgehog-GLI signaling pathway (Hh-GLI pathway)

The Hedgehog-GLI signaling pathway is not a single molecular target but a multi-component signal transduction cascade fundamental to embryonic development, adult tissue homeostasis, and cell fate determination[1][5]. The pathway is initiated by secreted ligands (Sonic, Indian, and Desert hedgehog), which bind to the Patched (PTCH1/PTCH2) receptors, releasing inhibition of the Smoothened (SMO) receptor, and culminating in the activation of the GLI family of transcription factors in the nucleus[1][2][3][5][7]. Dysregulation—either via overexpression, mutation, or autocrine/paracrine activation—contributes to a variety of diseases, most notably cancers such as basal cell carcinoma and medulloblastoma[2][7]. Multiple drugs targeting different components (most notably SMO and GLIs) have been developed and are in clinical use or under investigation, though challenges such as resistance and toxicity limit their broad application[2]. Hedgehog-GLI pathway activity is measured by GLI1/GLI2 mRNA and protein, among other target gene expression markers, which also serve as pharmacodynamic biomarkers in clinical trials[3]. Notably, the Hedgehog-GLI "signaling pathway" is a pathway, not a receptor, enzyme or single protein target, so while therapeutically actionable, the submitted name is not the canonical form for structured target databases.

Other names

Hedgehog pathwayHh signaling pathwaySonic Hedgehog pathwayHH-GLI signalingHh-GLI pathway

SMO inhibitors block SMO to prevent GLI activation (Vismodegib, Sonidegib); GLI inhibitors (Arsenic trioxide targets GLI1 directly); Ligand antagonism (Cyclopamine binds SMO and blocks downstream signaling); Pathway inhibition leads to impaired tumor growth, reduced proliferation, and increased apoptosis