RNA Methylationand Transcriptome Analysis RevealKey Regulatory Pathways Related to Cadmium-Induced Liver Damage

Cadmium (Cd) is a prevalent environmental and industrial contaminant that causes significant damage to liver function. However, the role of m⁶A methylationa critical epigenetic modificationin Cd-induced liver injury remains poorly understood. This study aimed to investigate the effects of m⁶A methylation in Cd-induced liver damage. A mouse model of Cd-induced liver injury was established, and exposure to CdCl₂ (20 mg/kg) for 90 days resulted in reduced m⁶A methylation levels. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-Seq), we characterized the m⁶A methylation profiles in both control and Cd-exposed groups. A total of 8355 unique m⁶A peaks and 1,101 unique m⁶A-modified genes were identified. Among these, 673 genes exhibited differential m⁶A methylated modifications, including 463 hyper-methylated and 210 hypo-methylated genes. Conjoint analysis of MeRIP-seq and RNA-Seq data unveiled genes that showed both differential methylation and expression. These genes were significantly enriched in the AGE-RAGE and PI3K-Akt signaling pathway. Through bioinformatics screening, five key genes (<i>Il-1β</i>, <i>Ccl2</i>, <i>Tlr2</i>, <i>Itgax</i>, and <i>Ccr2</i>) were identified, and expression validation indicated that <i>Itgax</i> and <i>Ccr2</i> may play pivotal roles in Cd-induced liver injury. Notably, elevated expression of methyltransferase-like 14 (METTL14) was observed in both in vivo and in vitro models. Inhibition of <i>Mettl14</i> can regulate Cd-induced liver inflammation through m⁶A-dependent regulation of <i>Ccr2</i> expression. Collectively, our findings highlight the crucial role of Mettl14 and Ccr2 in Cd-induced liver injury, providing novel insights into the epigenetic mechanisms underlying liver diseases and potential biomarkers for diagnosis and therapy.