ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a progressive, scarring lung disease that, while rare, significantly impacts survival for patients. The time to death from diagnosis for idiopathic pulmonary fibrosis patients is worse than most solid cancers (except lung and pancreas). Despite the impact of this condition, treatments only slow progression of the scarring in the lung and have yet to be able to impact survival or quality of life. The only “cure” for IPF remains lung transplantation, which has a 50% survival at 5-years despite the significant medical resources required. These patients need new therapies and deserve a better understanding of the disease to inform clinical practice. Therefore, the overall objective of this proposal is to identify novel mechanisms and markers of IPF lung injury. Our central hypothesis is that biologic and biochemical perturbations that occur in the lung microenvironment of IPF patients will elucidate novel mechanisms of lung injury in IPF to advance precision diagnostics and elucidate future targets to develop precise treatments. To begin to attain this overall objective, we will pursue the following two Specific Aims. Our first aim is to identify differences in spatial gene expression in areas of fibrosis and inflammation in lung tissue from IPF patients that correlate to survival. Our second aim is to identify differential protein and metabolite levels in BALF from IPF patients that correlate to survival. We propose to combine an established and well-characterized, large cohort of patients with a rare disease and stored samples that are no longer collected in modern clinical or research eras (surgical lung biopsy tissue) with cutting edge precision medicine tools like spatial transcriptomics and label-free quantitative proteomics and metabolomics. Importantly, this cohort has paired lung fluid samples (bronchoalveolar lavage fluid) which allows us to identify markers of these novel IPF phenotypes in the lung in a clinically accessible compartment via bronchoalveolar lavage. This innovative proposal will define groups of IPF patients with unique molecular and/or biologic pathways that can set the stage for prospective biomarker guided, therapeutic interventional trials. Additionally, these findings will help us understand for the first time how IPF patients with poor survival are different from those with better survival using precision medicine approaches at the individual molecular, protein and metabolite level.