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Under pathological conditions, systemic collapse of this defense network occurs through multiple interconnected mechanisms: epigenetic silencing (e.g., GPX4 promoter hypermethylation) impairs transcriptional activation (Wei et al., 2020), ROS overconsumption coupled with Nicotinamide Adenine Dinucleotide Phosphate (NADPH) deficiency and cysteine transport defects deplete GSH reserves, while electrophilic metabolites inactivate GPX4 via post-translational modification (Yang et al., 2022)

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