Recent Advances on the Molecular Mechanisms of Apoptosis Induced by Natural Product Oridonin and Its Derivatives

Oridonin, a bioactive ent-kaurane diterpenoid derived from Rabdosia rubescens, has attracted considerable attention as a promising anti-cancer candidate. Its diverse functional groups and favorable physicochemical properties provide multiple opportunities for structural modification, leading to the development of numerous derivatives with improved drug-likeness and enhanced therapeutic potential. Accumulating evidence indicates that oridonin and its derivatives exert potent anti-cancer effects across a broad spectrum of malignancies, primarily through the induction of RCD pathways, including apoptosis, autophagy, pyroptosis, and ferroptosis. Among these, apoptosis remains the most extensively studied mechanism, with mitochondrial dysfunction, BCL-2 family regulation, p53-MDM2 modulation, and NF-κB signaling suppression identified as critical molecular events. Additionally, novel derivatives have shown the capacity to overcome limitations of native oridonin, such as poor solubility, low bioavailability, and rapid clearance, thereby broadening its clinical potential. This review systematically summarizes recent advances in the structural modification of oridonin and the underlying molecular mechanisms of its anti-cancer activity, providing insights into the rational design of new oridonin-based therapeutics.