Pyroptosis- and Necroptosis-Related Signaling in Salicylate UV Absorber-Induced Toxicity: Implications for Sustainable Chemistry and Human Health

As emerging global environmental contaminants, organic ultraviolet absorbers (OUVAs) are widely used in personal care formulations and exhibit environmental persistence and potential bioaccumulation. Among these compounds, 2-ethylhexyl salicylate (EHS) and homosalate (HMS) are the most frequently used salicylate-type UV filters in cosmetic formulations. Although an increasing number of studies have demonstrated their environmental hazards, little is known about the molecular mechanisms underlying their cytotoxicity in mammalian systems, a fundamental knowledge gap for both human health protection and the development of more environmentally friendly consumer goods. In this study, we used mouse embryonic fibroblasts (MEFs, 3T6) and zebrafish as models to assess the toxicological phenotypes of EHS and HMS in vitro and in vivo, respectively. We found that both EHS and HMS induced cellular damage characterized by oxidative stress, disrupted intracellular calcium homeostasis, mitochondrial impairment, and DNA damage. Importantly, molecular analyses further suggested the concurrent activation of two distinct regulated cell death programs: pyroptosis, as suggested by Caspase-11-mediated GSDMD cleavage, and necroptosis, as suggested by ZBP1-RIPK3-Caspase-8-mediated MLKL phosphorylation. The in vitro data have been partially validated at the level of gene expression and in developmental toxicity in the zebrafish model, providing some in vivo phenotypic and molecular correlates. While the upstream events were experimentally verified, the causal links among them remain to be further elucidated. Taken together, this work suggested that OUVA-induced toxicity is not limited to isolated oxidative damage, but may also involve the activation of two different cell death programs. These findings provide important molecular clues to understanding the potential health and ecological risks of widely used UV filters and offer a scientific basis for their more environmentally friendly safety evaluation and regulatory management, which are crucial for advancing more sustainable chemistry and safer consumer goods.