Background <p>Lymphangioleiomyomatosis (LAM) is a rare, multisystemic metastatic disease. Chemokines are implicated in promoting LAM cell migration and tumor progression. Our prior plasma proteomics identified elevated C-C motif chemokine ligand 14 (CCL14) in LAM, yet its role remains unexplored.</p> Methods <p>Proteomic analysis identified CCL14 as differentially expressed in LAM patients versus healthy controls. Single-cell RNA sequencing (scRNA-seq) of lung tissues (six LAM patients, five healthy donors) identified the cellular source of CCL14 and explored its functional pathways bioinformatically. ELISA-quantified plasma CCL14 levels were analyzed for correlations with clinical phenotypes and longitudinal disease progression in 53 LAM patients and 25 controls.</p> Results <p>Proteomics and scRNA-seq revealed upregulation of CCL14 in LAM patients, primarily localized to lymphatic and vascular endothelial cells. Functional enrichment linked CCL14 to proliferative (mTORC1, MYC), inflammatory (TNF-α/NF-κB), and chemotactic pathways. CellPhoneDB indicated CCL14 mediates interactions between endothelial cells and innate immune/alveolar epithelial cells, and between endothelial cells themselves, via ACKR2, CCR3 and CCR1. Clinically, plasma CCL14 levels were significantly elevated in LAM patients versus controls (<i>p</i> = 0.003). Subgroup analyses demonstrated higher CCL14 levels in patients with angiomyolipomas (AMLs) versus those without, and in CT grade III versus grade I/II. Critically, CCL14 predicted disease progression: baseline CCL14 levels were higher in progressive versus stable patients (<i>p</i> = 0.0266) and positively correlated with annual increase in the percentage of cystic lung volume (<i>r</i> = 0.4051, <i>p</i> = 0.0446).</p> Conclusions <p>CCL14 is a critical regulatory molecule within the LAM microenvironment and a promising biomarker for disease severity and progression.</p>