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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 0.75). Single-cell analysis revealed differential immune cell infiltration, with Cluster 2 showing increased immune activity. COX6A1 knockdown in vitro alleviated palmitic acid-induced mitochondrial dysfunction and apoptosis, suggesting its potential as a therapeutic target. CONCLUSION: Our study found that COX6A1 is closely related to MASLD status and molecular subtypes, and it shows strong diagnostic value across independent cohorts. COX6A1 is associated with abnormal mitochondrial redox metabolism and immune regulation—particularly macrophage signaling—and its modulation directly affects lipotoxic injury (mtROS, ΔΨm, apoptosis) in hepatocyte models. Together, these findings nominate COX6A1 as a mechanistically grounded biomarker and a potential therapeutic target for MASLD.
Yu et al. (Mon,) studied this question.