Exploring Natural Products To Overcome Ferroptosis, A Form Of Cell Death Driven By Lipid Peroxidation

Abstract

Ferroptosis is a cell death modality driven by iron-dependent lipid peroxidation. Although lipid peroxidation can be initiated through several pathways (spontaneously via the Fenton reaction from the labile iron pool or enzymatically through lipoxygenases), the execution and propagation of ferroptosis rely on polyunsaturated fatty acids (PUFAs) esterified to membrane phospholipids or ether-linked to plasmalogens, along with compromised antioxidant defences. Over the past five years, research on ferroptosis has experienced an exponential growth, mainly due to its pathological implications, particularly in neurodegenerative diseases and its potential relevance in anti-cancer interventions. Given that neurons utilize iron to meet their metabolic requirements and harbor elevated levels of PUFAs, these brain cells are susceptible to ferroptosis. Thus, inhibition of this process could be an emerging and promising strategy in the treatment of neurodegenerative disorders. Accordingly, growing evidence points towards the regulation of lipid metabolism and redox signaling as new therapeutic avenues, the latter focusing on enhancing the cell’s intrinsic antioxidant capacity through synthetic radical- trapping agents, and glutathione-dependent support, such as GPX4 mimetics. In this work, we explored natural products and related derivatives as ferroptosis modulators in in vitro models associated with neurodegenerative processes related to iron accumulation. In ferroptotic stress scenarios, the natural sesquiterpene lactone deacylcynaropicrin effectively attenuates iron- induced lipid peroxidation and reactive oxygen species formation in human neuroblastoma and glial cells. Mechanistically, the compound promotes the nuclear translocation of the antioxidant transcription factor NRF2 and the upregulation of GCLc. NRF2 and its downstream gene GCLc are considered as the indirect regulatory sphere of ferroptosis. Furthermore, under ferroptotic stress, deacylcynaropicrin exhibited anti-inflammatory activity by suppressing NO production, preventing the nuclear translocation of the pro-inflammatory transcription factor NFκB, and downregulating COX-2 and IL-1β expression in macrophages and glial cells, while also attenuating astrocyte reactivity. Additionally, we constructed a library of triterpenoids and coumarins derivatives predicted in silico to cross the blood–brain barrier and tested them in dopaminergic neurons challenged with ferroptosis inducers, erastin and RSL3. Within this paradigm, we identified a synthetic coumarin–chalcone hybrid with significant anti-ferroptotic activity. In conclusion, our findings highlight natural products and their derivatives as promising scaffolds for ferroptosis inhibition. Deacylcynaropicrin and a coumarin-chalcone hybrid stand out as lead candidates for neuroprotective strategies in ferroptosis-associated neurodegeneration, warranting further mechanistic exploration and in vivo validation.