# SPHK1-S1p Signaling Drives Fibrocyte-Mediated Pulmonary Fibrosis: Mechanistic Insights and Therapeutic Potential

## TL;DR

This study identifies the SPHK1-S1P signaling pathway as a key driver of fibrocyte-mediated lung fibrosis and suggests it as a potential treatment target.

## Contribution

The study reveals SPHK1 as a novel genetic driver of idiopathic pulmonary fibrosis and identifies potential therapeutic strategies targeting the SPHK1-S1P axis.

## Key findings

- Targeting SPHK1 and S1PR1 reduced fibrocyte accumulation and lung fibrosis in a mouse model.
- SPHK1 was identified as a significant genetic driver of idiopathic pulmonary fibrosis.
- PAXX and RBKS were found to be downstream effectors of SPHK1 in fibrotic processes.

## Abstract

Background: Pulmonary fibrosis (PF) is a progressive interstitial lung disease characterized by chronic inflammation and excessive extracellular matrix deposition, with fibrocytes playing a pivotal role in fibrotic remodeling. This study aimed to identify upstream molecular mechanisms regulating fibrocyte recruitment and activation, focusing on the SPHK1 pathway as a potential therapeutic target. Methods: We utilized Mendelian Randomization and phenome-wide association analyses on genes involved in sphingolipid metabolism to identify potential regulators of idiopathic pulmonary fibrosis (IPF). A bleomycin-induced mouse model was employed to examine the role of the SPHK1-S1P axis in fibrocyte recruitment, using SKI-349 to target SPHK1 and FTY720 to antagonize S1PR1. Results: Our analyses revealed SPHK1 as a significant genetic driver of IPF. Targeting SPHK1 and S1PR1 led to a marked reduction in fibrocyte accumulation, collagen deposition, and histopathological fibrosis. Additionally, PAXX and RBKS were identified as downstream effectors of SPHK1. Our protein–protein interaction mapping indicated potential therapeutic synergies with existing anti-fibrotic drug targets. Conclusions: Our findings establish the SPHK1-S1P-S1PR1 axis as a key regulator of fibrocyte-mediated pulmonary fibrosis and support SPHK1 as a promising therapeutic target.