# Autocrine Netrin‐1 Signaling in Hepatic Stellate Cells Drives Liver Fibrosis and Diet‐Induced Metabolic Dysfunction‐Associated Steatohepatitis in Mice

## TL;DR

Netrin-1 signaling in liver cells worsens liver fibrosis and steatohepatitis in mice, suggesting a new target for treatment.

## Contribution

Identifies Netrin-1 as a novel autocrine driver of HSC activation and liver fibrosis in MASH.

## Key findings

- Netrin-1 overexpression in the liver worsens fibrosis in mice.
- Blocking Netrin-1 reduces liver fibrosis and MASH symptoms in experimental models.
- Netrin-1 activates HSCs via UNC5B receptors, promoting fibrogenic gene expression.

## Abstract

Liver fibrosis is a central feature of progressive liver diseases, including metabolic dysfunction‐associated steatohepatitis (MASH). The profibrotic liver microenvironment drives hepatic stellate cell (HSC) activation and collagen deposition. However, the nature of HSC‐mediated autocrine signaling during the fibrotic response has not been completely characterized. Here, we identify Netrin‐1 as an autocrine factor that drives HSC activation and liver fibrosis in patients with MASH. Hepatic Netrin‐1 expression was consistently elevated across multiple experimental models of liver fibrosis. Functional studies showed that adenovirus‐associated virus (AAV)‐mediated hepatic Netrin‐1 overexpression exacerbated fibrosis, whereas HSC‐specific conditional ablation of Netrin‐1 markedly attenuated diet‐induced MASH and CCl4‐induced liver fibrosis. Notably, lipid nanoparticle‐mediated siRNA knockdown of Netrin‐1 ameliorated liver fibrosis in mice. Mechanistic investigations revealed that Netrin‐1 promotes HSC activation through autocrine signaling mediated by the UNC5B receptor, which triggers rapid intracellular Ca2+ mobilization and downstream SMAD2 phosphorylation and fibrogenic gene expression. Collectively, our findings identify a novel autocrine signaling axis in which HSC‐derived Netrin‐1 establishes a positive feedback loop that sustains HSC activation and drives fibrotic progression. Blocking the Netrin‐1‐mediated fibrogenic response may offer a potential therapeutic strategy for anti‐fibrotic interventions.

Netrin‐1 expression is upregulated in hepatic stellate cells (HSCs) during metabolic dysfunction–associated steatohepatitis and injury‐mediated liver fibrosis. Secreted Netrin‐1 establishes an autocrine positive feedback loop by binding to UNC5B receptors on HSCs. Receptor activation triggers calcium influx and profibrotic response in HSCs, leading to increased extracellular matrix (ECM) production and liver fibrosis.