PGK1 lactylation-driven self-reinforcing loop orchestrates glycolytic reprogramming in FSP1+ macrophages in liver fibrosis

Background

Liver fibrosis is an excessive reparative response of the liver to chronic injury, characterized by aberrant extracellular matrix deposition, and its continuous progression can lead to cirrhosis and even hepatocellular carcinoma. Currently, there is a lack of effective therapeutic drugs for reversing liver fibrosis, and the molecular mechanisms underlying liver fibrosis require further investigation. Protein lactylation, a recently discovered posttranslational modification driven by the metabolite lactate, directly translates cellular metabolic status into signals that regulate protein function, serving as an important bridge connecting metabolic reprogramming and epigenetic regulation. FSP1 (fibroblastspecific protein 1) was originally considered a marker of fibroblasts, but recent studies have confirmed that it is primarily expressed by a proinflammatory macrophage subset in liver injury and participates in the regulation of inflammation and fibrosis. This study systematically explores the interplay among these three elements.

Research Progress

By integrating multi-omics analysis with clinical cirrhotic liver tissue samples, the researchers identified a pathogenic subset of FSP1⁺ macrophages as a key driver of liver fibrosis progression. They further uncovered a novel "FSP1glycolysislactylation" axis: FSP1 directly binds to pyruvate kinase M2 (PKM2) and stabilizes the protein by inhibiting its ubiquitinproteasome degradation, thereby enhancing glycolytic flux and lactate production. Accumulated lactate in turn promotes KAT2Bmediated lactylation of phosphoglycerate kinase 1 (PGK1) at lysine 353 (K353). This modification simultaneously activates PGK1 and pyruvate dehydrogenase kinase 1 (PDHK1), suppresses mitochondrial pyruvate metabolism, and establishes a positive feedback loop that continuously amplifies glycolysis and lactylation signaling. Notably, based on this mechanism, the team developed a cellpenetrating peptide targeting PGK1K353 lactylation, which effectively blocks fibrosis progression in multiple preclinical models of liver fibrosis, validating the feasibility of targeting lactylation as a therapeutic strategy for liver fibrosis (Fig. 1). This study not only deepens our understanding of the "metabolicimmune microenvironment" regulatory network in liver fibrosis but also provides new theoretical foundations and candidate drugs for precision intervention in chronic liver diseases.

Future Prospects

This study is the first to integrate macrophage metabolic reprogramming with PGK1 lactylation modification, demonstrating that the “FSP1glycolysisPGK1 lactylation” selfreinforcing loop is a key mechanism driving liver fibrosis progression (Figure 3). In terms of specific applications, this mechanism is not limited to liver fibrosis itself; the cellpenetrating peptide targeting PGK1 K353 lactylation (K353pe) has been validated in multiple animal models and 3D liver spheroid models, and its application can be extended to fibrotic diseases in other organs (e.g., pulmonary and renal fibrosis) as well as to the tumor microenvironment, where modulation of metabolicimmune crosstalk is needed. Furthermore, the levels of FSP1 and PGK1 K353 lactylation may serve as noninvasive diagnostic biomarkers for staging liver fibrosis, thereby providing new strategies for precision stratification and targeted intervention in chronic liver diseases.

Sources: https://spj.science.org/doi/10.34133/research.1177