Ursolic acid: context-dependent redox activity on oxidative stress and its toxicological implications

Oxidative stress is a major contributor to xenobiotic-induced tissue injury, mitochondrial dysfunction, inflammation, ferroptosis, and carcinogenesis. Ursolic acid (UA), a naturally occurring pentacyclic triterpenoid, has emerged as a context-dependent regulator of redox homeostasis. This review summarizes current evidence regarding the dual effects of UA on oxidative stress and its toxicological implications. Under non-malignant conditions, UA generally exerts antioxidant and cytoprotective effects in the majority of experimental models examined. Reduced reactive oxygen species (ROS) accumulation, modulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) signalin, preservation of mitochondrial homeostasis, and attenuation of inflammatory and apoptotic responses appear to underlie these protective activities. Protective effects have been reported in experimental models of hepatic, renal, cardiovascular, neurological, and radiation-associated injury. By contrast, in tumor cells characterized by elevated basal oxidative stress, UA has frequently been shown to exert pro-oxidative actions, though this response is influenced by concentration, exposure duration, and cellular context. In malignant models, UA has been shown to enhance ROS accumulation, disturb redox balance, suppress antioxidant defenses, and promote cell death associated with ferroptosis and apoptosis, thereby increasing sensitivity to chemotherapy and radiotherapy. Despite promising preclinical findings, several limitations continue to restrict clinical translation, including poor oral bioavailability, variable pharmacokinetics, potential herb-drug interactions, and insufficient long-term toxicological evaluation. Overall, current evidence supports UA as a context-dependent redox modulator with dual antioxidant and pro-oxidant activities, although further mechanistic, pharmacokinetic, and translational studies remain necessary.