Radio-labelled fibroblast activation protein inhibitors in interstitial lung diseases – a systematic review

• Published in: Autoimmunity reviews Vol. 24; no. 9; p. 103856
• Main Authors: Bundgaard-Nielsen, Mads, Johnsen, Rikke Helin, Mortensen, Jann, Shaker, Saher Burhan, Nielsen, Christoffer Tandrup Holst
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 29.08.2025
• Subjects: Allergy and Immunology; Animals; CTD-ILD; Disease Models, Animal; Endopeptidases; FAPI; Fibroblast activation protein inhibitor; Gelatinases - antagonists & inhibitors; Gelatinases - metabolism; Humans; Idiopathic Pulmonary Fibrosis; ILD; Interstitial lung disease; IPF; Lung - diagnostic imaging; Lung - pathology; Lung Diseases, Interstitial - diagnosis; Lung Diseases, Interstitial - diagnostic imaging; Lung Diseases, Interstitial - metabolism; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - metabolism; Mice; PET/CT; Pulmonary fibrosis; Radiopharmaceuticals; Serine Endopeptidases - metabolism; ILD; Pulmonary fibrosis; FAPI; PET/CT; Fibroblast activation protein inhibitor; CTD-ILD; Interstitial lung disease; IPF
• ISSN: 1568-9972; 1873-0183
• DOI: 10.1016/j.autrev.2025.103856

Currently, no tools can monitor ongoing fibrotic activity properly, making early identification of and timely therapeutic intervention with antifibrotics in patients with progressive fibrosing interstitial lung disease (ILD) difficult. Fibroblast activation protein-α inhibitor (FAPI) radiotracers could address these challenges. This review examines the association between pulmonary FAPI tracer uptake, fibrotic activity, and clinical parameters used for disease monitoring and prognostication in ILD to provide insights into its clinical potential. In January 2025, a systematic literature search on PubMed, Ovid Medline, and Cochrane Library, utilizing the block-search strategy and snowballing, was conducted, and 13 studies were included. Both murine and human studies support that FAPI tracer uptake reflects fibrotic activity in ILDs, as uptake was consistently elevated in subject groups compared to controls. In murine ILD models, increased uptake was associated with fibrosis and fibroblast activation protein-α (FAP-α) expression upon histological examination. Uptake preceded the development of fibrosis on computed tomography (CT) and attenuated once fibrosis was established. In human ILD patients (Idiopathic pulmonary fibrosis (IPF) = 55, Connective tissue disease (CTD) ILD = 68, other ILDs = 55), FAPI uptake was localized to fibrotic lesions on high-resolution computed tomography (HRCT) and associated with increased FAP-α expression ex vivo. Uptake correlated with baseline pulmonary function tests (PFTs) and fibrosis extent on HRCT. Increased FAPI tracer uptake at baseline predicted disease progression upon follow-up. An increasing body of evidence supports that FAPI tracers hold great clinical potential for the management of ILD by accurately monitoring fibrotic disease activity and identifying patients at risk of progression. Further research is required to confirm these findings. •FAPI radiotracers are markers of ongoing tissue fibrosis inILD•FAPI uptake correlates with fibrotic lesions on HRCT and reduced lung function•FAPI uptake is associated with progression of ILD and treatment failure to antifibrotics•FAPI PET/CT hold great potential to improve prognostication, monitoring, and treatment of ILD in the future