Metabolic Remodeling and Epigenetic Regulation: Novel Insights into Hepatic Fibrosis Mediated by Lactylation Modification

1. Literature Information

• Article Title: Metabolic Remodeling and Epigenetic Regulation: A Novel Interpretation of Hepatic Fibrosis Mechanism Based on Lactylation Modification
• Research Area: Metabolism, Epigenetics, Liver Fibrosis, Hepatic Stellate Cell (HSC) Fate Regulation
• Core Focus: Crosstalk between metabolic reprogramming and epigenetic modification; HK2‑mediated lactylation (H3K18la) in chromatin remodeling and HSC activation; therapeutic implications
• Key Methodology: Multi‑omics integration, epigenomic profiling, metabolic‑epigenetic axis analysis, molecular mechanism validation

2. Research Background

Hepatic fibrosis represents a progressive pathological process driven by persistent liver injury, characterized by excessive extracellular matrix deposition. Hepatic stellate cell (HSC) activation is the central driver of fibrogenesis. Emerging evidence reveals that metabolic reprogramming (especially aerobic glycolysis / Warburg effect) and epigenetic remodeling are tightly coupled in regulating HSC fate.

Lactate, once considered a waste product, is now recognized as a pivotal signaling metabolite that drives histone lactylation—a novel epigenetic mark that directly remodels chromatin state and gene expression. However, the regulatory network linking glycolysis, lactylation, chromatin accessibility, and HSC activation remains poorly defined. This study addresses this gap by dissecting the HK2–lactate–lactylation axis as a master regulator of liver fibrosis.

[Image: Crosstalk between metabolic reprogramming and epigenetic regulation in liver fibrosis]

3. Research Rationale

This study aimed to:

1. Reveal the regulatory role of metabolic reprogramming in epigenetic modification during hepatic fibrosis
2. Define the function of HK2‑mediated lactate production in histone lactylation (H3K18la)
3. Elucidate how lactylation remodels chromatin architecture and controls HSC activation
4. Identify key transcription factors and enzymatic crosstalk in the metabolic‑epigenetic axis
5. Propose novel therapeutic strategies targeting metabolic‑epigenetic crosstalk for fibrosis treatment

4. Key Research Findings

4.1 Lactylation: The Dual Coding Link Between Metabolism and Epigenetics

• Lactate derived from the Warburg effect acts as a critical substrate for histone lactylation (H3K18la).
• H3K18la is highly enriched in the promoter regions of pro‑fibrotic genes, directly activating transcription.
• Lactylation signaling promotes STAT3 nuclear translocation, establishing a feed‑forward activation loop.
• HK2‑dependent lactate accumulation locally inhibits HDAC activity, sustaining a hyper‑acetylated / hyper‑lactylated chromatin state.

4.2 Metabolic‑Epigenetic Network Governing HSC Fate

• HK2 subcellular redistribution: HK2 detaches from mitochondria and accumulates in the cytoplasm, boosting lactate production and nuclear translocation.
• Epigenetic memory via lactylation: H3K18la recruits PRC2 complexes to stabilize the pro‑fibrotic transcriptional program.
• Enzymatic crosstalk: Inactivated PKM2 relieves LSD1 inhibition, enhancing H3K4me2 demethylation and further remodeling chromatin.

4.3 Innovative Therapeutic Strategies Targeting Metabolic‑Epigenetic Axis

• Structure‑based HK2 allosteric inhibitors to block metabolic‑epigenetic signaling
• Lactylation‑specific antibody tools for early diagnosis and therapeutic monitoring
• Combination regimens using mTORC1 inhibitors plus HDAC modulators to reverse HSC metabolic phenotype

4.4 Conclusion

This work establishes a paradigm‑changing “metabolite–epigenetic modification–chromatin remodeling” regulatory axis in hepatic fibrosis. HK2‑driven lactylation acts as a central switch that integrates metabolic status with epigenetic gene regulation. These insights provide a mechanistic foundation for next‑generation anti‑fibrotic therapies.

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