SOCS1, SOCS2, and GADD45G represent a candidate senescence-related immune signature associated with MASLD, with macrophage-associated reduction in GADD45G and its modulation in vitro providing preliminary evidence for a potential role of GADD45G in MASLD-associated immune dysregulation.
Key Findings
Results
SOCS1, SOCS2, and GADD45G were identified as core senescence-related genes (SRGs) in MASLD through integrated transcriptomic analysis and machine learning.
Four transcriptomic datasets comprising 127 controls and 127 MASLD patients were integrated as the discovery cohort.
Candidate SRGs were identified through differential expression analysis, weighted gene co-expression network analysis (WGCNA), and three machine learning algorithms.
All three genes showed reduced expression in MASLD liver tissues compared to controls.
Their expression correlated with histological features of MASLD and immune alterations.
Results
The three-gene signature (SOCS1, SOCS2, GADD45G) demonstrated favorable classification performance for MASLD in both internal and external validation cohorts.
Classification performance was evaluated in internal and external cohorts beyond the discovery cohort.
Immune infiltration was assessed using CIBERSORT to characterize immune alterations associated with the signature.
The signature was described as showing 'favorable classification performance' in validation cohorts.
Results
GADD45G expression was decreased in high-fat diet (HFD)-induced obese mice at both mRNA and protein levels.
Experimental validation was performed in high-fat diet (HFD)-induced obese mice.
GADD45G showed reduced expression at both mRNA and protein levels in HFD mice.
Reduced immunoreactivity for GADD45G was observed specifically in F4/80-positive hepatic macrophages.
This finding links GADD45G downregulation to the macrophage compartment in a murine model of MASLD.
Results
Single-cell RNA sequencing analysis supported macrophage-associated expression of Gadd45g in hepatic cell populations.
Single-cell RNA sequencing analysis was performed on dataset GSE300744.
Analysis evaluated GADD45G distribution across hepatic cell populations.
Results 'further supported macrophage-associated expression of Gadd45g,' corroborating the in vivo immunohistochemical findings.
Results
Reduced GADD45G protein expression in palmitic acid (PA)-stimulated bone marrow-derived macrophages (BMDMs) was partially restored by camptothecin and myristicin treatment.
Experimental validation was performed in palmitic acid (PA)-stimulated BMDMs as an in vitro model of lipotoxic stress.
PA stimulation reduced GADD45G protein expression in BMDMs.
Treatment with camptothecin partially restored GADD45G protein expression.
Treatment with myristicin also partially restored GADD45G protein expression.
These compounds were identified as potential GADD45G-associated compounds through molecular docking prediction.
Results
Expression of SOCS1, SOCS2, and GADD45G correlated with immune alterations and immune cell infiltration patterns in MASLD liver tissues.
Immune infiltration was assessed using CIBERSORT algorithm.
Expression of the three SRGs correlated with histological features of MASLD.
The genes were linked to immune dysregulation in MASLD, suggesting a connection between senescence-related pathways and hepatic immune microenvironment.
The study framed these genes as 'senescence-related molecular nodes linking hepatic stress with immune dysregulation.'
What This Means
This research suggests that three genes — SOCS1, SOCS2, and GADD45G — play a role in the connection between cellular aging (senescence) and immune system dysfunction in metabolic dysfunction-associated steatotic liver disease (MASLD), a condition formerly known as non-alcoholic fatty liver disease. The researchers analyzed liver gene expression data from 127 patients with MASLD and 127 healthy individuals, using computational methods including machine learning to identify these three genes as consistently reduced in diseased liver tissue. Together, these three genes formed a molecular 'signature' that could distinguish MASLD patients from healthy controls in additional validation datasets.
A key focus was the gene GADD45G, which was found to be specifically reduced in liver macrophages — immune cells that reside in the liver and play important roles in inflammation. This finding held true both in mice fed a high-fat diet to model MASLD and in laboratory experiments using macrophages exposed to palmitic acid (a saturated fatty acid that mimics conditions in fatty liver disease). Importantly, two compounds — camptothecin and myristicin — were able to partially restore GADD45G levels in these stressed macrophages, suggesting these or similar compounds might be worth investigating further.
This research suggests that cellular senescence (a state where cells stop dividing but remain metabolically active and can promote inflammation) may contribute to MASLD through changes in immune cell behavior, particularly in liver macrophages. The identification of SOCS1, SOCS2, and GADD45G as a senescence-related immune signature provides potential targets for future research into MASLD diagnosis and treatment, though the authors note these findings are preliminary and further studies are needed to understand the functional consequences of these gene changes.