**Background:** The Hedgehog (HH) signaling pathway is an evolutionarily conserved cascade critical for embryonic development, tissue homeostasis, and cellular processes such as proliferation, differentiation, and epithelial-mesenchymal transition (EMT). Dysregulation of HH signaling is a major driver of tumorigenesis and malignancy in various cancers. This review aims to provide a comprehensive overview of HH signaling, its role in homeostasis and cancer, and the current state of targeted therapies.
**Methods:** This is a narrative review that synthesizes findings from a large body of published research, including in vitro and in vivo studies, clinical trials, and meta-analyses. The authors systematically describe the core components of the HH pathway (ligands Shh, Dhh, Ihh; receptors Ptch1/2, Smo; transcription factors Gli1-3; and co-receptors), the role of primary cilia in signal transduction, and the pathway's involvement in maintaining homeostasis in mesenchymal and epithelial tissues. They then review the evidence linking HH signaling to cancer initiation, progression, metastasis, stemness, and therapy resistance across multiple organ systems. Finally, they catalog targeted therapies, including small molecule inhibitors, natural compounds, and non-coding RNAs, and summarize clinical trial data.
**Key Results:** The review details that HH signaling is essential for homeostasis in bone (e.g., Ihh upregulates osteoblast markers; Gli1+ MSCs regulate calvarial bone formation), muscle (Shh promotes myosatellite cell proliferation and differentiation), skin (Shh maintains hair follicle stem cells), intestine (Ihh is essential for intestinal stem cell regeneration), and lung (Shh regulates epithelial-mesenchymal interactions). In cancer, aberrant HH signaling is implicated in numerous malignancies. For example, in basal cell carcinoma (BCC), 90% of sporadic cases carry somatic Ptch mutations, leading to ligand-independent Smo activation. In medulloblastoma, Ptch1 mutations are found in ~45% of Shh-subtype cases. In pancreatic ductal adenocarcinoma, high Shh and Gli1 expression are independent prognostic factors for worse survival. The review also highlights that HH signaling contributes to drug resistance in many cancers, such as through Gli-mediated regulation of ABC transporters in triple-negative breast cancer and through EMT induction in non-small-cell lung cancer. For targeted therapies, the FDA-approved Smo inhibitors vismodegib and sonidegib show objective response rates of 47.6% and 57.6% for locally advanced BCC, respectively. However, acquired resistance due to Smo mutations (e.g., D473H) is a clinical challenge. Newer inhibitors like taladegib, LEQ-506, and TAK-441 are effective against some resistant mutants. Gli inhibitors such as arsenic trioxide (ATO) and GANT61 show preclinical efficacy, and ATO is approved for acute promyelocytic leukemia. Natural compounds like vitamin D3 and itraconazole also inhibit HH signaling and are in clinical trials.
**Clinical Implications:** The review underscores the critical role of HH signaling in cancer and the potential of targeting this pathway for therapy. The approval of Smo inhibitors for BCC and the ongoing clinical trials for other cancers (e.g., medulloblastoma, AML, pancreatic cancer) demonstrate translational progress. However, the emergence of drug resistance, particularly to Smo inhibitors, necessitates the development of next-generation inhibitors targeting downstream components like Gli or alternative pathways. The review also emphasizes the need for combination therapies (e.g., with chemotherapy, targeted agents, or immunotherapy) to improve efficacy and overcome resistance. A deeper understanding of the precise mechanisms of HH signaling in different cancer contexts will be essential for optimizing therapeutic strategies and improving patient outcomes.