Iron overload disrupts lipid desaturation through SKN-1 signaling in C. elegans: implications for ferroptosis-based...

The field of biomaterials is shifting from bioinert designs toward bioactive and responsive systems, as exemplified by ferroptosis-inducible immunomodulatory adjuvants. Although these platforms enable programmed immune responses, their metallic components introduce distinct risks. Degradation or wear releases free metal ions (e.g., irons) that disrupt local and systemic metal homeostasis, particularly iron metabolism. This unintended disturbance of the immune-iron axis may act as a "secondary hit", promoting a pathological microenvironment that compromises therapeutic efficacy and accelerates disease progression. Using Caenorhabditis elegans as a simplified yet physiologically informative model, we show that iron overload, mimicking long-term biomaterial exposure, leads to chronic toxicity, metabolic dysregulation, and mitochondrial dysfunction. Moreover, we identify a regulatory interplay between the fatty acid desaturases fat-5/fat-7 and the cytoprotective transcription factor skn-1 (the Nrf2 ortholog) under high-iron conditions. These findings underscore the importance of evaluating long-term metabolic consequences in biomaterial safety assessments and suggest potential lipid-centric strategies to mitigate iron-associated chronic toxicity and iron-overload disorders.