The dual face of safranal: Neuroprotective antioxidant or mitochondrial uncoupler?

Mitochondrial dysfunction and redox imbalance lie at the core of neurodegenerative and inflammatory pathologies. Safranal, a monoterpene aldehyde from Crocus sativus L., exhibits paradoxical biological behavior-serving as a neuroprotective antioxidant at physiological doses and a mitochondrial disruptor under excessive exposure. This review integrates mechanistic, omics, and computational evidence to delineate the biphasic nature of safranal's actions across cellular contexts. At low concentrations, safranal enhances PI3K/Akt/GSK3β, Nrf2/HO-1, and SIRT1/PGC-1α pathways, stabilizing mitochondrial membrane potential, suppressing NF-κB and NLRP3 inflammasome activation, and promoting neuronal survival. Conversely, high-dose exposure induces mitochondrial uncoupling, ROS amplification, p53/JNK/p38 MAPK activation, and apoptotic or ferroptotic cell death. Multi-omics analyses reveal reciprocal regulation of phosphorylation and acetylation networks, while AI-based modeling identifies distinct attractor states defining safranal's hormetic window. We propose a systems-level framework in which safranal functions as a dose-dependent mitochondrial switch, channeling redox flux toward adaptation or collapse depending on metabolic context. Translational strategies-including nanocarrier encapsulation and co-therapeutic combinations-may enable precise delivery of safranal within its hormetic window for neurodegeneration and oncology.