Xenoferroptosis, a double-hit challenge for regulated cell death

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.