Background: Cystogenesis and interstitial fibrosis are contributing factors to kidney failure in individuals with autosomal dominant polycystic kidney disease (ADPKD). The molecular and cellular mechanisms involved in cyst growth and fibrosis are complex and new therapies are urgently needed to improve clinical outcomes. Methods: We used mass spectrometry-based proteomics to identify molecular changes in the Pkd1nl/nl mouse model of ADPKD and selected integrin-α1 as a candidate of interest to follow up in functional studies. Mice lacking integrin-α1 (Itga1-/-) were crossed to Pkd1nl/nl mice and effects on kidney function and kidney histology were measured. We investigated the effects of integrin-α1 depletion on fibrosis markers using qRT-PCR, western blot and immunofluorescence. Results: Proteomic analysis of the Pkd1nl/nl mouse showed increased abundance of integrin-α1. In human ADPKD tissue and two single cell RNA kidney disease datasets, ITGA1 was also upregulated. To investigate the functional role of this integrin subunit in ADPKD, we generated a Pkd1nl/nlItga1-/- mouse. We observed a significant reduction in kidney volume and kidney dysfunction in Pkd1nl/nl mice lacking integrin-α1. Kidneys from Pkd1nl/nlItga1-/- mice had smaller cysts, reduced interstitial expansion and less tubular atrophy. The myofibroblast marker alpha-smooth muscle actin remained switched on in Pdgfrb+ stromal cells of Pkd1nl/nlItga1-/- kidneys, suggesting integrin-α1 is not needed for activation of fibroblasts. Analysis of cell proliferation markers suggested that integrin-α1 promoted fibroblast expansion in response to cystic injury. Conclusions: These results highlight a previously unrecognised role for integrin-α1 in cyst growth and fibrosis in polycystic kidney disease.