Associations between cuprotosis-related genes and the spectrum of metabolic dysfunction-associated fatty liver disease: An exploratory study

Aims: To explore the associations between cuprotosis-related genes (CRGs) acrossdifferent stages of liver disease in metabolic dysfunction-associated fatty liver disease(MAFLD), including hepatocellular carcinoma (HCC). Materials and Methods: We analysed several bulk RNA sequencing datasets frompatients with MAFLD (n=331) and MAFLD-related HCC (n=271) and two MAFLDsingle-cell RNA sequencing datasets. To investigate the associations between CRGsand MAFLD, we performed differential correlation, logistic regression and functionalenrichment analyses. We also validated the findings in an independent WenzhouPERSONS cohort of MAFLD patients (n=656) used for a genome-wide associationstudy (GWAS). Results:GLS,GCSHandATP7Bgenes showed significant differences across theMAFLD spectrum and were significantly associated with liver fibrosis stages.GLSwasclosely associated with fibrosis stages in patients with MAFLD and those withMAFLD-related HCC.GLSis predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver tometabolic-associated steatohepatitis,GLSexpression in T cells decreased. GWASrevealed that multiple single nucleotide polymorphisms inGLSwere associated withclinical indicators of MAFLD. Conclusions:GLSmay contribute to liver inflammation and fibrosis in MAFLD mainlythrough cuprotosis and T-cell activation, promoting the progression of MAFLD toHCC. These findings suggest that cuprotosis may play a role in MAFLD progression,potentially providing new insights into MAFLD pathogenesis.