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

<b>Background:</b> 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 <i>SPHK1</i> pathway as a potential therapeutic target. <b>Methods:</b> 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 <i>SPHK1-S1P</i> axis in fibrocyte recruitment, using SKI-349 to target <i>SPHK1</i> and FTY720 to antagonize <i>S1PR1</i>. <b>Results:</b> Our analyses revealed <i>SPHK1</i> as a significant genetic driver of IPF. Targeting <i>SPHK1</i> 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 <i>SPHK1</i>. Our protein-protein interaction mapping indicated potential therapeutic synergies with existing anti-fibrotic drug targets. <b>Conclusions:</b> Our findings establish the <i>SPHK1-S1P-S1PR1</i> axis as a key regulator of fibrocyte-mediated pulmonary fibrosis and support <i>SPHK1</i> as a promising therapeutic target.