Aims: Non-enzymatic autoxidation of polyunsaturated fatty acids (PUFAs), generating numerous toxic by-products implicated in neurodegeneration, aging, and other pathologies, is a key process in ferroptosis. Lipid peroxidation (LPO) can be inhibited by deuterated polyunsaturated fatty acids (D-PUFA), as the rate-limiting step of abstraction of bis-allylic hydrogen atoms is slowed down by replacing the bis-allylic hydrogens with deuteriums. Here, we aimed to assess the protective effect of monounsaturated fatty acids (MUFA), which do not undergo LPO, as compared to that of various D-PUFAs, in a liposomal model of LPO.

Methods: To detect LPO induced by ferrous ions in liposomes, we used the LPO fluorescent probe C11-Bodipy (581/591), in addition to measuring conjugated diene and malondialdehyde accumulation.

Results: By applying the C11-Bodipy (581/591) probe, we found that both 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and 1-stearoyl-2-(11,11-d₂-linoleoyl)-phosphatidylcholine (D2-Lin-PC) protect non-deuterated 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine (H-Lin-PC) liposomes from LPO. Similarly, both POPC and 1-stearoyl-2-(11,11,14,14-D4-linolenyl)-phosphatidylcholine (D4-Lnn-PC) protect 1-stearoyl-2-linolenyl-phosphatidylcholine (H-Lnn-PC), and so does 1-stearoyl-2-(6,6,9,9,12,12,15,15,18,18-d10-docosahexaenoyl)-sn-glycero-3-phosphatidylcholine (D10-DHA-PC). The conjugated diene and malondialdehyde probes also showed similar protective effects of POPC and D-PUFA on LPO in H-Lnn-PC.

Conclusion: Obviously, the presence of non-oxidizable lipids, such as POPC, similar to the deuterated lipids D2-Lin-PC, D4-Lnn-PC, and D10-DHA-PC, leads to a sharp decrease in the length of lateral propagation of chain reactions in lipid membranes, but they do not participate in LPO themselves.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Recent evidence indicates that ferroptosis is a critical player associated with cell death and inflammatory processes in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, as well as in chronic inflammation. In addition, during aging, the expression and activity of various proteins and cellular processes associated with the ferroptotic pathway, such as lipid peroxidation, have been shown to be altered. In this review, we introduce the concept of xenoferroptosis, a process in which ferroptotic signalling is amplified through the combined action of distinct challenges: one involving sub-threshold ferroptosis-related mechanisms, and another involving sub-toxic levels of exogenous or endogenous stressors. Exogenous challenges, such as air pollutants, pesticides, and micro- or nanoplastics, can disrupt redox balance through increased reactive oxygen species production, and impaired antioxidant defences. Endogenous triggers could include misfolded, aggregated proteins, such as amyloid-beta, hyperphosphorylated tau, and alpha-synuclein, which sensitize cells by promoting redox imbalance and mitochondrial dysfunction. While each individual stressor, either endogenous/exogenous or ferroptotic-associated process, may be sublethal, their convergence would initiate a synergistic cascade that accelerates cell death. We propose that xenoferroptosis represents a distinct pathogenic axis at the intersection of molecular pathology and environmental exposure, offering new perspectives for therapeutic interventions that target its dual-trigger mechanisms.

Ferroptosis, an iron-dependent form of regulated cell death (RCD) driven by lipid peroxidation, has been extensively studied since its conceptualization in 2012 and has been suggested as a therapeutic target in many cancers and degenerative diseases. However, three fundamental questions remain unanswered about ferroptosis. First, the mechanisms by which cells execute death during ferroptosis remain elusive: The key role of lipid peroxides in triggering ferroptosis is established, but how this results in the death of a cell remains unclear. Second, the physiological role of ferroptosis throughout the human life cycle is unclear; currently, there is evidence for ferroptosis in early development, immunity, aging, and tumor suppression, but not in many other aspects of physiology. Third, and finally, the intersection between ferroptosis and other RCD modalities, such as apoptosis, necroptosis, pyroptosis, and autophagic cell death, is necessary for understanding how ferroptosis integrates into networks controlling cellular fate. Addressing these gaps in knowledge is essential for building a comprehensive understanding of this mode of cell death, as well as translating ferroptosis knowledge into effective therapeutics.