RNA Methylation and Transcriptome Analysis Reveal Key Regulatory Pathways Related to Cadmium-Induced Liver Damage

  • Chem Res Toxicol. 2025 Apr 21;38(4):717-732. doi: 10.1021/acs.chemrestox.4c00539.
Hao Huang  1 ,  Guoliang Li  2 ,  Sihui Guo  1 ,  Kaile Li  1 ,  Wei Li  1 ,  Qinwen Zhou  1 ,  Zhini He  1 ,  Xingfen Yang  1 ,  Lili Liu  2 ,  Qinzhi Wei  1
Affiliations
  • 1. School of Public Health, Food Safety and Health Research Center, Guangdong Provincial Key Laboratory of Tropical Disease Research, Southern Medical University, Guangzhou 510515, China.
  • 2. Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Department of Toxicology, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510300, China.
PMID: 40135526 DOI: 10.1021/acs.chemrestox.4c00539
Abstract

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 (Il-1β, Ccl2, TLR2, Itgax, and CCR2) were identified, and expression validation indicated that Itgax and CCR2 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 Mettl14 can regulate Cd-induced liver inflammation through m6A-dependent regulation of CCR2 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.

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