Hepatitis B virus X protein-Sonic Hedgehog signaling pathway (HBx-SHH pathway)

The Hepatitis B virus X protein-Sonic Hedgehog signaling pathway (HBx-SHH pathway) represents a crucial signaling axis in the pathogenesis of Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The viral HBx protein acts as a potent activator of the Sonic Hedgehog (SHH) pathway by upregulating SHH ligands and directly interacting with or stabilizing GLI transcription factors, particularly GLI1 and GLI2 [2, 8, 13]. This aberrant activation facilitates tumor growth, epithelial-mesenchymal transition (EMT), and the maintenance of cancer stem cells, which are associated with increased invasiveness and recurrence [1, 5, 6]. Therapeutic targeting of this axis primarily involves the use of small-molecule inhibitors of Smoothened (SMO), such as vismodegib and sonidegib, to block the transmission of the hedgehog signal to the nucleus [3, 4, 12]. Although primarily studied in the context of basal cell carcinoma, these inhibitors have shown promise in preclinical models for reducing the progression of HBx-mediated liver cancer [2, 13]. Key challenges include the development of drug resistance through SMO mutations and significant side effects such as teratogenicity and muscle toxicity [15, 17].

Other names

HBx-Hedgehog signaling axisHepatitis B virus X protein-mediated Sonic Hedgehog signalingHBV X protein-SHH axis

Inhibition of the Smoothened (SMO) receptor or GLI transcription factors to block the downstream transcriptional activity of the Hedgehog pathway that is aberrantly activated by the viral HBx protein.