<p>This study aimed to elucidate the mechanism by which decorin (DCN)⁺ colony-stimulating factor 1 (CSF1)⁺ fibroblasts exacerbate alveolar inflammation and fibrosis in acute respiratory distress syndrome (ARDS) through the TGF-β signaling pathway and to clarify the dual role of DCN protein in this process. Lung tissues from LPS-induced ARDS and control mice were subjected to single-cell RNA sequencing (scRNA-seq). Raw sequencing reads were processed exclusively with Cell Ranger, whereas HISAT2 and StringTie were used only in preliminary bulk RNA-seq trials and were excluded from the single-cell analytical pipelines. Differential expression was assessed with MAST using thresholds of |log2FC| &gt; 1 and <i>P</i> &lt; 0.05. Gene Ontology (GO) enrichment analysis was conducted using the clusterProfiler R package (v4.0). 3T6-SWISS ALBINO cells were transduced with lentiviral vectors to establish a stable human DCN-overexpressing cell line. scRNA-seq identified a DCN⁺CSF1⁺ fibroblast subset with elevated expression of pro-inflammatory genes, including <i>Nfkb1</i>, <i>Il1b</i>, and <i>Ccl2</i>. Pseudotime analysis indicated progressive activation of the TGF-β signaling pathway within the DCN⁺CSF1⁺ subpopulation, including significant upregulation of <i>Tgfb1</i> and its receptor <i>Tgfbr1</i>, suggesting that DCN⁺CSF1⁺ fibroblasts promote pulmonary fibrosis through an autocrine/paracrine TGF-β-Tgfbr1 loop. Immunohistochemistry confirmed increased expression of the myofibroblast-specific marker α-SMA and the mesenchymal marker N-cadherin in lung tissues from mice with ARDS. In vitro experiments further showed that elevated human DCN expression reduced the expression of key interstitial cell markers, including α-SMA, vimentin, and N-cadherin, implying that human DCN may mitigate pulmonary fibrosis by suppressing fibrotic molecular programs. These findings highlight the role of the DCN⁺CSF1⁺ fibroblast subset in ARDS-associated fibrosis and suggest new therapeutic targets.</p>