Repurposing Pentacyclic Triterpenoids as Ferroptosis Inducing Agents for Cancer Therapies

Purpose of review: Cancer continues to be a significant global health challenge and one of the leading causes of mortality worldwide. Natural product drug screens have been incentivized for new classes of anticancer agents with potential pharmacological activity as inducers of ferroptosis. Pentacyclic triterpenoids experimentally exhibit broad-spectrum antineoplastic activities. Nevertheless, an updated review of their effects and mechanisms, particularly in connection with ferroptosis and related oxidative stress processes, is overdue. Recent findings: Ferroptosis, an iron-dependent form of regulated cell death, is triggered by reactive oxygen and nitrogen species (ROS/RNS) and lipid peroxidation, compromising cancer cell membrane integrity. Due to elevated Fe²⁺ uptake, metabolically active or proliferating cancer cells are highly susceptible to ferroptosis, making it a promising therapeutic target for overcoming chemoresistance and metastasis. Pentacyclic triterpenes, bioactive compounds from plants and fungi, have emerged as potent pro-ferroptotic agents in preclinical studies. Compounds like celastrol and ursolic acid induce ferroptosis in various cancers such as hepatocellular carcinoma, pancreatic, gastric, breast, cervical, glioblastoma, and leukemia by disrupting glutathione (GSH)-dependent antioxidant defenses and the Keap1-Nrf2 pathway. Recent findings further suggest the possibilities of exploring pentacyclic triterpenes as novel candidate drugs or adjuvants in conjunction with the use of conventional anticancer drugs in various treatment modalities such as chemotherapy, immunotherapy and radiotherapy. Summary: Certain cellular features of ferroptosis are mechanistically relevant to the design of therapeutic strategies against proliferating cancer cells, as documented in recent studies on pentacyclic triterpenoids. These compounds thus carry potential for preclinical and clinical applications across diverse cancers.