YTHDC2 mediated RNA m⁶A modification contributes to PM_2.5-induced hepatic steatosis

Exposure to fine particulate matter (PM_2.5) is a significant risk factor for hepatic steatosis. The N⁶-methyladenosine (m⁶A) is implicated in metabolic disturbances triggered by exogenous environmental factors. However, the role of m⁶A in mediating PM_2.5-induced hepatic steatosis remains unclear. Herein, male C57BL/6J mice were subjected to PM_2.5 exposure throughout the entire heating season utilizing a real-ambient PM_2.5 whole-body inhalation exposure system. Concurrently, HepG2 cell models exposed to PM_2.5 were developed to delve the role of m⁶A methylation modification. Following PM_2.5 exposure, significant hepatic lipid accumulation and elevated global m⁶A level were observed both in vitro and in vivo. The downregulation of YTHDC2, an m⁶A-binding protein, might contribute to this alteration. In vitro studies revealed that lipid-related genes CEPT1 and YWHAH might be targeted by m⁶A modification. YTHDC2 could bind to CDS region of them and increase their stability. Exposure to PM_2.5 shortened mRNA lifespan and suppressed the expression of CEPT1 and YWHAH, which were reversed to baseline or higher level upon the enforced expression of YTHDC2. Consequently, our findings indicate that PM_2.5 induces elevated m⁶A methylation modification of CEPT1 and YWHAH by downregulating YTHDC2, which in turn mediates the decrease in the mRNA stabilization and expression of these genes, ultimately resulting in hepatic steatosis.