Background <p>The clinical management of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is challenging due to its heterogeneous progression. While recent studies have shown that pulmonary uptake of ¹⁸F-FDG and ⁶⁸Ga-FAPI on positron emission tomography (PET) may indicate ILD activity, the spatial distribution of their molecular targets—GLUT1, GLUT3, and FAPα—in SSc-ILD lung tissue is largely unexplored. Here, we investigate the expression patterns of these markers across varying fibrosis stages in lung tissue of SSc-ILD patients and controls to improve PET interpretation.</p> Methods <p>Immunohistochemistry for GLUT1, GLUT3, and FAPα was performed on lung tissue from SSc-ILD patients (<i>n</i> = 9) and controls (<i>n</i> = 8). Fibrosis stage and cell-type-specific expression of these markers were analyzed by 2 experienced ILD pathologists, and quantitative staining was assessed using QuPath software. Marker expression was analyzed in and compared between areas with varying fibrosis stages.</p> Results <p>GLUT1 positive cells were primarily erythrocytes, GLUT3 positive cells were mainly myeloid cells and FAPα positive cells were predominantly fibroblasts, endothelial cells, epithelial cells, and macrophages. All cells positive for these markers were more present in SSc-ILD compared to controls, with GLUT1 and FAPα positive cells showing highest prevalence in areas with early signs of fibrosis.</p> Conclusions <p>The prevalence of cells expressing GLUT1 and FAPα is increased in areas with early signs of fibrosis and the expression of GLUT1, GLUT3 and FAPα is observed in different cell types suggesting that ¹⁸F-FDG and ⁶⁸Ga-FAPI PET each may be useful to visualize different aspects of ILD activity.</p>