Ion channel gene signature for diagnosis and antifibrotic therapy in liver fibrosis

Abstract Background Liver fibrosis (LF) is a progressive pathological process that may lead to cirrhosis and liver failure. Human ion channel genes (HICGs) participate in hepatic mechanotransduction and immune regulation, but their contributions to LF remain insufficiently characterized. This study aimed to profile the expression of HICGs in LF and to identify key genes with diagnostic and therapeutic relevance. Methods Multiple transcriptomic datasets were integrated to identify differentially expressed HICGs in LF. Weighted gene co-expression network analysis and single-cell RNA sequencing were applied to identify fibrosis-associated gene modules and cell-type distribution. Functional enrichment and immune infiltration analyses were performed to explore biological relevance. The expression of key genes was validated in human cirrhotic tissues and bile duct ligation mouse models using immunohistochemistry. Potential therapeutic compounds targeting hub HICGs were predicted through molecular docking simulations. Results Three HICGs— AQP1 , GJA1 , and KCNN2 —were identified as fibrosis-associated hub genes, showing distinct expression patterns and high diagnostic performance. GJA1 showed consistent upregulation in both experimental models and human cirrhosis. Functional analyses linked these genes to extracellular matrix remodeling, cell adhesion, and cytokine interactions, while immune infiltration analysis revealed significant associations with M0 macrophages, plasma cells, NK cells, and memory B cells. Molecular docking simulations further identified 16 candidate drugs targeting KCNN2 and GJA1. Conclusions This study demonstrates that AQP1 , GJA1 , and KCNN2 are closely associated with LF progression and immune remodeling. The consistent upregulation of GJA1 , together with the identification of candidate drug interactions, provides potential avenues for biomarker development and therapeutic repurposing in LF.