# CXCL1 Promotes Fibrotic Remodeling in Atrial Fibrillation via Activation of TXNDC5 and Endoplasmic Reticulum Stress

## TL;DR

This study shows that CXCL1 contributes to atrial fibrosis in atrial fibrillation by activating ER stress and TXNDC5, suggesting a new treatment target.

## Contribution

The novel contribution is identifying the CXCL1–ERS–TXNDC5 pathway as a driver of atrial fibrosis in AF.

## Key findings

- CXCL1 levels are elevated in patients with atrial fibrillation.
- CXCL1 induces fibrosis and activates ER stress markers and TXNDC5 in cardiac fibroblasts.
- Inhibiting ER stress or silencing TXNDC5 reduces CXCL1-induced fibrosis.

## Abstract

Atrial fibrosis is a key structural substrate in atrial fibrillation (AF). This work was conducted to investigate the profibrotic effects of chemokine C-X-C motif Ligand 1 (CXCL1) and elucidate the actions of endoplasmic reticulum stress (ERS) and ER-resident protein thioredoxin domain-containing Protein 5 (TXNDC5) in this process.

Serum CXCL1 concentrations were measured in patients with AF and healthy controls. The effects of CXCL1 on atrial fibrosis were evaluated using ex vivo rat atrial tissue culture. Additionally, the influence of CXCL1 on collagen synthesis, ERS activation, and TXNDC5 expression was assessed in primary rat cardiac fibroblasts. Pharmacological inhibition of ERS and gene silencing of TXNDC5 were employed to decipher underlying mechanisms.

CXCL1 levels were elevated in patients with AF compared to controls. In ex vivo rat atrial tissue, CXCL1 treatment induced marked fibrosis and upregulated the expression of ERS markers GRP78 and ATF6, as well as TXNDC5. In cardiac fibroblasts, CXCL1 promoted the secretion of Collagen I, Collagen III, and TGF-β1. Notably, both ERS inhibition and TXNDC5 knockdown effectively attenuated CXCL1-induced fibroblast activation and extracellular matrix protein expression.

CXCL1 promotes atrial fibrosis through the activation of ERS and upregulation of TXNDC5, potentially contributing to atrial remodeling and the pathogenesis of AF. Targeting the CXCL1–ERS–TXNDC5 axis may offer a novel therapeutic approach for preventing and treating AF-related atrial fibrosis.