Phospholipid POPE calms activated liver cells in fibrosis study

A new multi-omics study of liver fibrosis reports that the disease is marked by coordinated, cell-type-dependent remodeling of lipid and energy metabolism, and that a specific phospholipid, a phosphatidylethanolamine species known as POPE, can reduce the activation of hepatic stellate cells in laboratory experiments.

The research, published as an open-access research article in the journal Biological Research on 28 September 2026, was led by Taoying Chen, Bin Du, Ning Wang and colleagues, with Sheng Cheng as senior author. The team set out to define how proteins, metabolites and cell-type-specific gene expression change together in liver fibrosis, a process the authors note remains incompletely understood.

To build the molecular picture, the researchers established a carbon tetrachloride-induced hepatic fibrosis model in mice and validated it by histology and serum markers. They then applied integrated proteomics, metabolomics and single-cell transcriptomics to profile molecular and metabolic changes, using pathway enrichment analyses based on KEGG, GO and MBROLE, together with network analyses including Ingenuity Pathway Analysis.

The integrated analysis identified coordinated disorders of arachidonic acid, retinol, linoleic acid, arginine-proline and butanoate metabolism in fibrotic livers. Network analysis highlighted PPARα and ERK1/2 as hub regulators, and pharmacological intervention confirmed their direct participation in hepatic stellate cell activation, the process by which these cells drive scar formation.

The study found that fibrotic liver tissue showed widespread suppression of hepatocyte cytochrome P450 enzymes, disrupted arachidonic acid and retinoid metabolism, and an accumulation of glycerophospholipids, including phosphatidylethanolamine. Although total phosphatidylethanolamine levels rose in fibrotic liver tissue, the authors report that exogenous POPE significantly inhibited hepatic stellate cell activation in their experiments.

Mechanistically, the researchers traced how POPE acted on activated stellate cells. According to the results, POPE suppressed the MAPK pathway, upregulated PPARα, and restored the excessive mitochondrial respiration and glycolysis that characterize activated hepatic stellate cells. Functional validation in hepatic stellate cells included western blot, qPCR, immunofluorescence and Seahorse assays, which measure cellular energy metabolism.

Extracellular matrix genes were mainly expressed in hepatic stellate cells, adhesion and cytoskeletal genes in macrophages, and downregulated cytochrome P450 genes in hepatocytes. The authors report that these metabolic molecular alterations were consistent with transcriptomic trends observed in human liver samples with advanced fibrosis, drawn from public datasets of patients with metabolic-associated steatohepatitis, also known as MASH or MASLD.

The authors conclude that hepatocyte-associated cytochrome P450 suppression, altered hepatic stellate cell bioenergetics and dysregulated glycerophospholipid metabolism collectively contribute to the fibrotic metabolic landscape. They describe POPE as being associated with reduced stellate cell activation and normalization of MAPK, PPARα and bioenergetic responses, identifying defined phosphatidylethanolamine species as potential modulators of hepatic stellate cell state.

The team is careful to frame the therapeutic implications as preliminary. In their conclusions, the authors state that further mechanistic and in vivo studies are required to determine the causal and therapeutic relevance of these findings. The published version is also an early-release, peer-reviewed accepted manuscript that remains subject to further edits before the final version of record replaces it.

For researchers studying fibrosis, the work offers a consolidated map linking metabolic pathway disruption to specific liver cell types, and a candidate lipid species whose effects on stellate cell activation and energy metabolism can now be tested in more demanding experimental settings.

Subject of Research: Multi-omics characterization of metabolic reprogramming in liver fibrosis and the effects of the phospholipid POPE on hepatic stellate cell activation

Article Title: Glycerophospholipids and energy remodeling orchestrate metabolic reprogramming in liver fibrosis

Article References: Chen, T., Du, B., Wang, N., Yuan, Y., Liu, Y., Tang, L., Tian, S., Zhang, X., Zhang, Z., Wu, J., Chen, J., Quan, Y., Han, B., & Cheng, S. (2026). Glycerophospholipids and energy remodeling orchestrate metabolic reprogramming in liver fibrosis. Biological Research. https://doi.org/10.1186/s40659-026-00728-4

Image Credits: AI Generated

DOI: 10.1186/s40659-026-00728-4

Keywords: liver fibrosis, hepatic stellate cells, glycerophospholipids, phosphatidylethanolamine, POPE, metabolomics, proteomics, single-cell transcriptomics, PPARα, MAPK pathway, cytochrome P450, mitochondrial respiration