Background <p>Interstitial lung diseases (ILDs) are a heterogeneous group of disorders with diverse clinical trajectories, highlighting the need for reliable biomarkers for prognostic assessment and risk stratification.</p> Methods <p>Single-cell RNA sequencing (scRNA-seq) was performed on explanted lung tissue from 3 patients with idiopathic pulmonary fibrosis (IPF) and 3 control subjects.</p> <p>Secreted phosphoprotein 1 (SPP1) was identified and further validated in serum samples from two ILD cohorts comprising 74 patients with IPF and 92 with idiopathic inflammatory myopathy-associated ILD (IIM-ILD), as well as 56 healthy controls (HCs). Patients with IPF were further classified as acute exacerbation (AE) or stable IPF, and patients with IIM-ILD as rapidly progressive (RP) or stable IIM-ILD. The association between serum SPP1 levels and 1-year all-cause mortality was assessed using Cox proportional hazards models.</p> Results <p>scRNA-seq demonstrated that SPP1 expression was markedly upregulated in explanted lungs from IPF patients compared with controls. Serum SPP1 levels were significantly higher in patients with ILD than in HCs (<i>P</i> &lt; 0.001), and were further elevated in AE-IPF (<i>P</i> &lt; 0.001), RP-IIM-ILD (<i>P</i> &lt; 0.001), and anti-melanoma differentiation-associated gene 5-positive IIM-ILD (<i>P</i> = 0.015). The 1-year mortality rates were 35.1% in patients with IPF and 31.5% in those with IIM-ILD. In multivariable Cox analyses, serum SPP1 was an independent predictor of 1-year mortality in the overall ILD cohort (hazard ratio [HR] 1.007, 95% confidence interval [CI] 1.002–1.012, <i>P</i> = 0.005), as well as in the IPF (HR 1.015, 95% CI 1.003–1.027, <i>P</i> = 0.012) and IIM-ILD (HR 1.007, 95% CI 1.001–1.012, <i>P</i> = 0.022) subgroups.</p> Conclusions <p>Serum SPP1 may serve as a potential biomarker for risk stratification and prognostic assessment in IPF and IIM-ILD.</p>