Metabolic Remodeling and Epigenetic Regulation: A Novel Interpretation of Hepatic Fibrosis Mechanism Based on Lactylation Modification

This paper focuses on the interaction between metabolic reprogramming and epigenetic modification, using hepatic fibrosis as a model to elucidate how hexokinase 2 (HK2)-mediated lactylation modification reshapes chromatin status and regulates the fate determination of hepatic stellate cells (HSCs). Through multi-omics integration analysis, we reveal the dual functions of glycolytic metabolic intermediates as epigenetic signaling molecules: they serve as direct substrates for histone lactylation (H3K18la) and reshape chromatin accessibility through metabolic enzyme activity regulation, providing an innovative molecular mechanism explanation for metabolism-driven fibrotic pathological processes.

I. Remodeling of the Metabolic Microenvironment: The Dual Coding Effect of Lactylation

1.1 Lactate, as a key metabolic product of the Warburg effect (i.e., aerobic glycolysis), activates histone lactylation modification enzyme complexes through non-canonical pathways, forming a metabolic-epigenetic regulatory axis.

1.2 Differential lactylation landscapes reshape chromatin three-dimensional structure: H3K18la is specifically enriched in the promoter regions of fibrosis-related genes, activating the nuclear entry signal of transcription factor STAT3.

1.3 Epigenetic reprogramming driven by metabolic intermediate concentration gradients: A high HK2 expression microenvironment forms a local lactate pool, maintaining an inhibitory state of histone deacetylase (HDAC) activity.

II. Metabolic Regulatory Networks Governing the Fate Determination of Hepatic Stellate Cells

2.1 Subcellular Relocalization of the Glycolytic Rate-Limiting Enzyme HK2: Transition from mitochondrial anchoring to cytoplasmic free state, enhancing lactate production and nuclear import efficiency.

2.2 Epigenetic Memory Effects of Lactylation Modification: H3K18la stabilizes the HSC activation phenotype by recruiting the PRC2 complex, forming a positive feedback loop.

2.3 Co-evolution of Metabolic Enzymes and Epigenetic Modification Enzymes: PKM2 phosphorylation inactivation relieves inhibition of LSD1, enhancing H3K4me2 demethylation and reshaping chromatin status.

III. Novel Therapeutic Strategies Targeting Metabolic Epigenetic Regulation

3.1 Design of Allosteric Inhibitors of HK2 Based on Structural Biology: Blocking the HK2-histone interaction interface to disrupt the lactylation modification cascade reaction.

3.2 Lactylation-Specific Antibody Chip Technology: Enabling early warning of HSC activation and dynamic monitoring of therapeutic response.

3.3 Clinical Translation Potential of Metabolic Remodeling Interventions: Combining mTORC1 inhibitors with HDAC activators to reshape the HSC metabolic phenotype and overcome the bottleneck in anti-fibrotic treatment.

Conclusion

This study constructs a systematic regulatory network of "metabolic intermediates-epigenetic modification-chromatin remodeling," elucidating the spatiotemporal-specific role of HK2-mediated lactylation modification in the pathological process of hepatic fibrosis. It provides a theoretical basis and technical support for the development of precision treatment strategies based on metabolic epigenetic regulation. This model can be extended to other metabolic-related disease fields, providing a paradigm reference for understanding the core role of metabolic reprogramming in epigenetic regulation.

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