Identification of Lactate-related Biomarkers in Non-alcoholic Fatty Liver Disease.
TL;DR
These findings bridge the gap between metabolic lipotoxicity and epigenetic regulation, suggesting that lactylation acts as a critical driver in NAFLD pathogenesis.
Abstract
Background
Nonalcoholic fatty liver disease (NAFLD) is characterized by profound metabolic reprogramming. Recent evidence suggests that lactate, beyond its role as a metabolic waste product, may modulate histone lactylation, linking metabolic stress to the epigenetic regulation of disease progression. However, the specific lactate-related gene (LRG) signatures driving NAFLD remain to be elucidated.
Methods
We integrated transcriptomic mining of the GSE164760 dataset with in vivo validation to decode the LRG landscape. Differentially expressed LRGs were identified using strict thresholds and subsequently intersected with the GeneCards database. Functional enrichment (GO/KEGG) and Protein-Protein Interaction (PPI) networks were constructed to screen for hub genes. Key biomarkers were subsequently corroborated in a high-fat diet (HFD)- induced rat NAFLD model via Western blotting.
Results
A total of 98 differentially expressed LRGs were identified, which were primarily enriched in molecular catabolism and xenobiotic stress responses. From this network, eight pivotal hub genes were distilled: CREBBP, EP300, HDAC1, HIF1A, PARP1, SIRT1, STAT3, and TP53. Diagnostic modeling demonstrated their predictive value, with AUC scores ranging from 0.60 to 0.81, among which PARP1 and STAT3 exhibited high diagnostic potential (AUC > 0.80). Experimental validation in the rat model confirmed the disruption of this metabolic-epigenetic regulatory module, revealing significant dysregulation in protein expression that reflects a compensatory stress response to lipotoxicity.
Discussion
These findings bridge the gap between metabolic lipotoxicity and epigenetic regulation, suggesting that lactylation acts as a critical driver in NAFLD pathogenesis.
Conclusion
This study delineates a preliminary, hypothesis-generating lactate-associated gene signature in NAFLD, highlighting a complex regulatory network governing hepatocyte metabolic plasticity and survival. These eight core biomarkers offer promising tissue-based targets for mechanistic intervention, though further validation in peripheral blood is required to establish their non-invasive diagnostic utility.