SelenomethionineAlleviates 6PPDQ-Induced Liver Inflammationby Targeting ROS/METTL3/YTHDC1/ATF3 Axis

Abstract 6PPD-quinone (6PPDQ), a tire-derived environmental toxicant, is closely associated with liver injury, but its toxicological mechanisms remain unclear. Selenium (Se), an essential trace element with antioxidant and cytoprotective properties, has shown potential in mitigating chemically induced liver injury. In this investigation, the protective effects of Se supplementation in 6PPDQ-induced hepatotoxicity were examined and the underlying mechanisms were elucidated by constructing both mice and AML12 cell models. The results demonstrated that 6PPDQ promotes liver inflammation by activating necroptosis. ATF3, a stress-inducible transcription factor, served as a key mediator of 6PPDQ-induced liver necroptosis. ATF3 nuclear translocation was driven by ROS and its expression regulated by METTL3/YTHDC1-mediated m6A methylation. Notably, selenomethionine (SeMet) effectively alleviated 6PPDQ-induced liver necroptosis by reducing ROS production, thereby suppressing ATF3 nuclear translocation and inhibiting the METTL3/YTHDC1-mediated m6A modification. These findings provide novel mechanistic insights into 6PPDQ hepatotoxicity and highlight the protective role of selenium against environmentally induced liver damage.