Targeting the PKC-Gli Axis: Bryostatin 1 as a Hedgehog Pathway Inhibitor.

Aberrant Hedgehog (Hh) signaling contributes to multiple cancers, yet current Smoothened (Smo)-targeted therapies are limited by resistance and relapse. This study investigates bryostatin 1, a clinically relevant natural product from Bugula neritina, for its ability to inhibit Hh signaling downstream of Smo. Bryostatin 1 robustly suppresses Gli transcriptional activity and significantly reduces the expression of key Hh pathway components in a time- and dose-dependent manner. Additionally, it selectively impairs viability in Hh-driven cancer cells while sparing healthy fibroblasts. These compelling results highlight bryostatin 1 as a promising therapeutic candidate for overcoming resistance in aggressive Hh-driven diseases.