PGK1 Lactylation-Driven Self-Reinforcing Loop Orchestrates Glycolytic Reprogramming in FSP1+ Macrophages in Liver
Min Tang1, Mengxue Sun1, Hui Zhang2
1Department of Gastroenterology and Hepatology, Digestive Disease Institute, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Research (Washington, D.C.)
|March 5, 2026
Summary
Researchers identified a new FSP1+ macrophage pathway driving liver fibrosis through enhanced glycolysis and lactylation. Targeting this pathway with a novel peptide effectively reduced fibrosis progression in preclinical models.
Area of Science:
- Immunology
- Metabolic reprogramming
- Epigenetics
Background:
- Liver fibrosis treatment is limited, with metabolic and epigenetic factors playing key roles.
- The specific contribution of lactate-mediated lactylation to the hepatic microenvironment is not fully understood.
Purpose of the Study:
- To identify novel therapeutic targets for liver fibrosis.
- To elucidate the role of lactate-mediated lactylation in fibrotic progression.
- To investigate the FSP1-glycolysis-lactylation axis in metabolic-immune crosstalk.
Main Methods:
- Integrative analysis of public databases and human cirrhotic liver tissues.
- Myeloid-specific Fsp1 knockout mouse models.
- Mechanistic investigations of protein interactions (FSP1-PKM2) and posttranslational modifications (PGK1 lactylation).
- Development and testing of a cell-penetrating peptide targeting PGK1 lactylation.
Main Results:
- A pathogenic FSP1+ macrophage subset was identified as a key therapeutic target.
- The FSP1-glycolysis-lactylation axis was uncovered, driving fibrotic progression.
- FSP1 stabilizes PKM2 in macrophages, enhancing glycolysis and lactate production.
- KAT2B-dependent lactylation of PGK1 at K353 creates a positive feedback loop, amplifying glycolysis.
- A peptide targeting PGK1-K353 lactylation attenuated liver fibrosis progression.
Conclusions:
- Lactate-mediated lactylation of PGK1 is a critical node in fibrotic metabolism.
- The FSP1-glycolysis axis sustains the pro-fibrotic microenvironment.
- Targeting PGK1-K353 lactylation offers a promising therapeutic strategy for chronic liver diseases.
Related Concept Videos
01:25cAMP-dependent Protein Kinase Pathways
8.8K
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
8.8K
01:24Liver Regeneration
4.6K
The liver is an important organ in vertebrates that plays an essential role in metabolism. It is also responsible for storing and redistributing nutrients such as carbohydrates, fats, and vitamins in the body. Additionally, the liver releases bile salts which are critical for digesting food and eliminating toxic metabolites from the body.
Cells of Liver
The liver comprises four major types of cells— hepatocytes, stellate, Kupffer, and sinusoidal endothelial cells. The hepatocytes are...
Cells of Liver
The liver comprises four major types of cells— hepatocytes, stellate, Kupffer, and sinusoidal endothelial cells. The hepatocytes are...
4.6K
01:22PI3K/mTOR/AKT Signaling Pathway
6.0K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
6.0K
01:58Cell Specific Gene Expression
16.8K
Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
16.8K
01:29Somatic to iPS Cell Reprogramming
2.7K
Reprogramming alters the gene expression in somatic cells, transforming them into induced pluripotent stem (iPS) cells over several generations. Scientists can reprogram cells by introducing genes for four transcription factors—Oct4, Sox2, Klf4, and c-Myc (OSKM) by viral or non-viral methods. These factors are also known as Yamanaka factors after Shinya Yamanaka, who first generated iPS cells using mouse skin cells. Yamanaka was awarded the Nobel Prize in Physiology or Medicine in 2012...
2.7K
01:09GPCRs Regulate Adenylyl Cylase Activity
7.9K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
7.9K