Current molecular medicine · 2026
Integrative Analysis Identifies Key Genes Associated with Immune Responses in Non-Alcoholic Fatty Liver Disease Via Single-Cell Sequencing and Bulk RNA Analysis.
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Shen Nan, Bi Binghan, Fang Yucheng, Miao Hongyu, Pu Peimin, Liu Zhidong, Yu Xiao, Xing Lianjun
Аннотация
INTRODUCTION: Liver inflammation in Non-Alcoholic Fatty Liver Disease (NAFLD) is shaped by immune regulation. This study examines the contribution of immune-related genes to NAFLD pathogenesis.
METHODS: Single-cell analysis identified key immune cell clusters and subtypes. Differential expression, machine learning, and expression profiling were used to screen key genes, which were then used to construct a nomogram predicting NAFLD risk. Immune infiltration analysis characterized immune states, and pseudotime analysis tracked key gene expression along T-cell differentiation. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to validate gene expression.
RESULTS: T cells were identified as the key immune cells, with regulatory T cells (Tregs) as the critical subtype. CXCR4, DUSP1, and ID2 were downregulated in NAFLD and supported a nomogram with good predictive performance. Immune infiltration analysis showed differences in six immune cell types, including Tregs, between NAFLD and controls. Pseudotime analysis showed increased CXCR4, DUSP1, and ID2 expression in Tregs and cytotoxic T lymphocytes (CTLs) at late differentiation, while NAFLD samples showed reduced DUSP1 and ID2 expression in RT-qPCR and Western blot assays.
DISCUSSION: Treg-centered immune dysregulation and the downregulation of CXCR4, DUSP1, and ID2 are closely linked to NAFLD pathology. The context-dependent nature of these genes precludes simple protective or pathogenic labels. The nomogram capturing single-cell-derived immune signatures outperforms conventional clinical predictors and offers mechanistic insight. Pseudotime analysis provides the first continuous view of T-cell activation trajectories in NAFLD. A ceRNA network involving NEAT1/XIST and miR-15b-5p may explain DUSP1 suppression. However, small validation cohorts (n = 3/group), the absence of functional experiments, and PBMC-based profiling limit causal inference; replication in larger intrahepatic cohorts is necessary before clinical translation.
CONCLUSION: T cells, especially Tregs, and CXCR4, DUSP1, and ID2 are central to Non-Alcoholic Fatty Liver Disease and may serve as diagnostic and therapeutic targets.
METHODS: Single-cell analysis identified key immune cell clusters and subtypes. Differential expression, machine learning, and expression profiling were used to screen key genes, which were then used to construct a nomogram predicting NAFLD risk. Immune infiltration analysis characterized immune states, and pseudotime analysis tracked key gene expression along T-cell differentiation. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting were used to validate gene expression.
RESULTS: T cells were identified as the key immune cells, with regulatory T cells (Tregs) as the critical subtype. CXCR4, DUSP1, and ID2 were downregulated in NAFLD and supported a nomogram with good predictive performance. Immune infiltration analysis showed differences in six immune cell types, including Tregs, between NAFLD and controls. Pseudotime analysis showed increased CXCR4, DUSP1, and ID2 expression in Tregs and cytotoxic T lymphocytes (CTLs) at late differentiation, while NAFLD samples showed reduced DUSP1 and ID2 expression in RT-qPCR and Western blot assays.
DISCUSSION: Treg-centered immune dysregulation and the downregulation of CXCR4, DUSP1, and ID2 are closely linked to NAFLD pathology. The context-dependent nature of these genes precludes simple protective or pathogenic labels. The nomogram capturing single-cell-derived immune signatures outperforms conventional clinical predictors and offers mechanistic insight. Pseudotime analysis provides the first continuous view of T-cell activation trajectories in NAFLD. A ceRNA network involving NEAT1/XIST and miR-15b-5p may explain DUSP1 suppression. However, small validation cohorts (n = 3/group), the absence of functional experiments, and PBMC-based profiling limit causal inference; replication in larger intrahepatic cohorts is necessary before clinical translation.
CONCLUSION: T cells, especially Tregs, and CXCR4, DUSP1, and ID2 are central to Non-Alcoholic Fatty Liver Disease and may serve as diagnostic and therapeutic targets.