# Acetyl-CoA acyltransferase 2 palmitoylation drives liver fibrosis by inducing hepatic stellate cell ferroptosis

## TL;DR

The study shows that ACAA2 palmitoylation promotes liver fibrosis by causing cell death in liver cells, suggesting it could be a new target for treatment.

## Contribution

The paper identifies ACAA2 palmitoylation as a novel driver of liver fibrosis through ferroptosis and proposes it as a potential therapeutic target.

## Key findings

- ACAA2 inhibition reduces ferroptosis and fibrosis in preclinical models.
- ACAA2 palmitoylation regulates its localization and function in hepatic stellate cells.
- Blocking ACAA2 palmitoylation suppresses fibrogenesis via AMPK pathway activation.

## Abstract

Hepatic fibrosis is a major driver of mortality in metabolic dysfunction-associated steatotic liver disease (MASLD)—previously known as non-alcoholic fatty liver disease (NAFLD). While hepatic stellate cell (HSC) activation and myofibroblast accumulation are central to fibrogenesis, the regulatory mechanisms remain incompletely understood. Acetyl-CoA acyltransferase 2 (ACAA2), a pivotal enzyme in fatty acid oxidation, has been implicated in lipid metabolism but has not been investigated as a therapeutic target in MASLD. Here, we show that ACAA2 upregulation in HSCs exacerbates hepatic fibrosis by promoting ferroptosis-associated transcriptional programs, whereas ACAA2 inhibition attenuates both ferroptosis and fibrogenesis in preclinical models. Mechanistically, ACAA2 palmitoylation governs its subcellular localization and function, and blocking this modification suppresses HSC activation via AMPK pathway stimulation, thereby mitigating fibrosis. Our study establishes ACAA2 palmitoylation as a druggable node for antifibrotic therapy, offering novel insights into metabolic regulation of hepatic fibrosis.

Image 1

•Hepatocyte-specific ACAA2 suppression attenuates ferroptosis and liver fibrosis through AMPK-mediated signaling.•ACAA2 ablation in hepatic stellate cells (HSCs) directly impedes their activation and profibrotic phenotype.•Palmitoylation-dependent regulation of ACAA2 drives ferroptosis progression and fibrogenesis.•Inhibition of ACAA2 ameliorates fibrosis in both carbon tetrachloride (CCl4) and metabolic dysfunction-associated steatohepatitis (MASH) murine models.

Hepatocyte-specific ACAA2 suppression attenuates ferroptosis and liver fibrosis through AMPK-mediated signaling.

ACAA2 ablation in hepatic stellate cells (HSCs) directly impedes their activation and profibrotic phenotype.

Palmitoylation-dependent regulation of ACAA2 drives ferroptosis progression and fibrogenesis.

Inhibition of ACAA2 ameliorates fibrosis in both carbon tetrachloride (CCl4) and metabolic dysfunction-associated steatohepatitis (MASH) murine models.