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Liver Disease Diagnosis and Treatment / Liver Diseases and Immunity · Journal article
Biomolecules · August 7, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is an integrative transcriptomic study that identifies SOCS1, SOCS2, and GADD45G as a senescence-related gene signature associated with immune dysregulation in MASLD, validated across transcriptomic datasets and supported by murine and in vitro experiments. The work provides candidate biomarkers and a potential mechanism linking hepatic senescence to macrophage dysfunction, but lacks direct evidence of clinical utility or functional proof of causation.
Integrated transcriptomic discovery with machine learning, in silico validation, and experimental validation in animal and cell models. Discovery: 127 MASLD patients and 127 healthy controls from integrated transcriptomic datasets. Experimental: high-fat diet-induced obese mice and bone marrow-derived macrophages from mice stimulated with palmitic acid. Intervention: High-fat diet in mice; palmitic acid stimulation in BMDMs; camptothecin and myristicin treatment in PA-stimulated BMDMs. Compared with: Normal diet controls in mice; unstimulated BMDMs; untreated PA-stimulated BMDMs.
SOCS1, SOCS2, and GADD45G identified as core senescence-related genes with reduced expression in MASLD liver tissues Three-gene signature showed favorable classification performance in internal and external validation cohorts In HFD-induced obese mice, GADD45G expression was decreased at mRNA and protein levels with reduced immunoreactivity in F4/80-positive hepatic macrophages
No clinical outcomes (fibrosis progression, cirrhosis, mortality) reported
This signature may serve as a future biomarker for identifying MASLD patients with immune dysregulation, but the findings remain exploratory and require human mechanistic studies and clinical outcome validation before informing clinical decisions.
Integrative transcriptomic and experimental study identifying a three-gene signature in MASLD with in vitro validation and murine model support, but lacking human clinical outcome data or mechanistic proof of causation.
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This signature may serve as a future biomarker for identifying MASLD patients with immune dysregulation, but the findings remain exploratory and require human mechanistic studies and clinical outcome validation before informing clinical decisions.
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Senescence-related molecular nodes linking hepatic stress with immune dysregulation in metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly defined. This study aimed to identify and experimentally validate a senescence-related gene (SRG) signature associated with immune dysregulation in MASLD. Four transcriptomic datasets (127 controls, 127 MASLD) were integrated as the discovery cohort. Candidate SRGs were identified through differential expression analysis, weighted gene co-expression network analysis, and three machine learning algorithms. Immune infiltration was assessed using CIBERSORT, and a three-gene signature was evaluated in internal and external cohorts. Potential GADD45G-associated compounds were predicted by molecular docking. Experimental validation was performed in high-fat diet (HFD)-induced obese mice and palmitic acid (PA)-stimulated bone marrow-derived macrophages (BMDMs). Single-cell RNA sequencing analysis of GSE300744 was further performed to evaluate GADD45G distribution in hepatic cell populations. SOCS1, SOCS2, and GADD45G were identified as core SRGs. Their expression was reduced in MASLD liver tissues and correlated with histological features and immune alterations. The three-gene signature showed favorable classification performance in validation cohorts. In HFD mice, GADD45G expression was decreased at both mRNA and protein levels, with reduced immunoreactivity in F4/80-positive hepatic macrophages. Single-cell analysis further supported macrophage-associated expression of Gadd45g. In PA-stimulated BMDMs, reduced GADD45G protein expression was partially restored by camptothecin and myristicin treatment. Overall, SOCS1, SOCS2, and GADD45G represent a candidate senescence-related immune signature associated with MASLD. The macrophage-associated reduction in GADD45G and its modulation in vitro provide preliminary evidence for a potential role of GADD45G in MASLD-associated immune dysregulation.
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