Differential effects of two Zn sources (ZnO nanoparticles and ZnSO4) on lipid metabolism via the ferroptosis pathway and SLC7A11K23 acetylation by HDAC8 and HDAC6 in a freshwater teleost

Abstract

Understanding the toxicity and hazard risk of various metal sources is very important and can provide new insights for their risk evaluation in the environment. At present, few studies have been performed to compare the differential mechanisms of ZnSO₄ and ZnO nanoparticles (ZnO NPs), two commonly distributed environmental pollutants, on hepatic damage and lipid metabolism, considering that parameters relevant to lipid metabolism have been broadly used as biomarkers for the risk evaluation of hazardous materials. Our findings revealed that, compared to the control without extra Zn addition, ZnO NPs increased the hepatic Zn content, promoted lipogenesis, and inhibited lipolysis; in contrast, ZnSO₄ increased hepatic Zn levels but suppressed lipogenesis and facilitated lipolysis. Further, ZnO NPs caused mitochondrial damage and lipid deposition through inducing ferroptosis, while ZnSO₄ promoted mitochondrial function and lipolysis by suppressing ferroptosis. Mechanistically, the ZnO NPs downregulated the HDAC8 protein level, while ZnSO₄ upregulated the HDAC6 expression. Both HDAC8 and HDAC6 interacted with the N-terminus of SLC7A11 and catalyzed the deacetylation of SLC7A11 at K23. SLC7A11 deacetylation at K23 inhibited ZnO NPs-induced ferroptosis and lipid deposition. However, SLC7A11 K23 deacetylation enhanced the inhibitory effect of ZnSO₄ on ferroptosis, thereby promoting ZnSO₄-induced lipolysis. Thus, our study elucidated the mechanisms by which ZnO NPs and ZnSO₄ differentially impacted hepatic lipid metabolism through ferroptosis and highlighted the critical role of SLC7A11 K23 acetylation in this process, which provided a novel mechanism for lipid metabolism and its regulation in vertebrates.