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

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. 1. Iron-overload decreased lifespan in C. elegans. 2. Iron-overload induced lipid overload, mitochondrial dysfunction and oxidative stress in C. elegans. 3. Stearoyl-CoA desaturase fat-5 and fat-7 regulated the response of iron-overload via skn-1 pathway in C. elegans.