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Nanoplastic-induced NAT10/ac4C axis drives both oxidative stress and chemoresistance
Summary
Researchers discovered that polystyrene nanoplastics trigger an epitranscriptomic stress response in cells by activating the enzyme NAT10, which hypermodifies transfer RNA with N4-acetylcytidine (ac4C) marks — and found this same pathway also reduces the effectiveness of the cancer drug sorafenib by nearly fourfold, establishing a direct link between nanoplastic exposure and impaired chemotherapy response.
The exact molecular mechanisms of nanoplastics toxicity remain poorly understood. This study provides the first evidence that exposure to polystyrene nanoparticles (PS-NPs) induces a significant epitranscriptomic reprogramming, detecting 38 different tRNA mononucleotides and 49 oligonucleotides through a derivatization-LC-MS/MS approach. PS-NPs induced potent oxidative stress, marked by a 3.1-fold increase in reactive oxygen species (ROS) and a 2.6-fold increase in the RNA damage marker 8-oxo-GMP. Furthermore, this stress upregulated the acetyltransferase NAT10, leading to N4-acetylcytidine (ac4C) hypermodification that occurred specifically within the D-loop of tRNA under nanoplastics stress. Interestingly, NAT10/ac4C axis activation could also decrease the sensitivity to the chemotherapeutic agent sorafenib, increasing its IC from 6.9 μM to 25.7 μM. Crucially, this chemoresistance was reversed by both pharmacological inhibition (with Remodelin) and genetic knockdown (with siRNA) of NAT10, which subsequently ameliorated oxidative stress and re-sensitized the cells to sorafenib, confirming the pathway's causal role in modulating cellular response to nanoplastic exposure. Our findings establish the upregulation of the NAT10/ac4C axis as a targeted, adaptive response to nanoplastics-induced stress, revealing a direct mechanistic link between an environmental pollutant and impaired chemotherapeutic efficacy. This identifies the NAT10/ac4C axis as both a key mediator of nanoplastics toxicity and a promising therapeutic target to restore cellular health.