A novel palmitoylation-based molecular signature reveals COX6A1 as a key regulator in metabolic dysfunction-associated steatotic liver disease

作者：Tianqi Yu, Zhihao Fang, Yue Cheng, Yongxu Zhou, Yanchao Ji, Chang Liu · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-07253-0 · 被引用次数：9 · 研究领域：Single-cell and spatial transcriptomics、Liver Diseases and Immunity、Liver Disease Diagnosis and Treatment

BACKGROUND: Metabolic dysfunction–associated steatotic liver disease (MASLD) is highly prevalent, but the molecular links between palmitoylation, mitochondrial function, and immune remodeling remain unclear. METHODS: We integrated four GEO bulk RNA-seq cohorts (GSE126848, GSE130970, GSE135251, GSE213621) and one single-cell RNA-seq cohort (GSE136103). Expression matrices were normalized to TPM, log-transformed, and batch-corrected with ComBat. A curated set of palmitoylation-related genes (PRGs) was assembled from GeneCards and used for consensus clustering (ConsensusClusterPlus) to define MASLD subtypes. Differential expression (limma; |log2FC|>0.5, P < 0.05), functional enrichment (clusterProfiler for GO/KEGG), and GSEA were performed. WGCNA identified PRG-associated modules; hub genes were prioritized using a machine-learning pipeline (12 algorithms; 113 model combinations) with 10-fold cross-validation in GSE213621 and external validation in GSE126848, GSE130970, and GSE135251. Immune infiltration was inferred using xCell, EPIC, MCP-counter, QUANTISEQ, CIBERSORT, and TIMER. In vitro, HepG2 cells exposed to palmitic acid were transfected with COX6A1 siRNA; lipid accumulation (Oil Red O/Nile Red), mitochondrial membrane potential (JC-1), mitochondrial ROS (MitoSOX), apoptosis (Annexin V/PI flow cytometry), and COX6A1/NDUFA4 expression (qRT-PCR/Western blot) were assessed. Performance was evaluated by ROC AUC and decision-curve analysis. RESULTS: Two MASLD subtypes, Cluster ...