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Mechanical forces arising from tissue heterogeneity are thought to influence the progression of idiopathic pulmonary fibrosis (IPF), but their impact under physiological variability remains unclear. We developed a multi-scale computational model of the human lung by embedding a micromechanical alveolar model within a gravitationally stratified lung model. Physiological variability was incorporated through a Monte Carlo uncertainty quantification of material and geometric parameters derived from clinical and literature data. Simulations were performed for three scenarios: healthy lung (H), uniformly fibrotic lung (UIPF), and heterogeneously fibrotic lung with a stiff base and compliant apex (SWIPF). The model’s predictions of macroscopic lung volumes showed strong quantitative agreement with clinical data. Notably, the predicted mean total lung capacity (TLC) for the SWIPF model (3.89 L) differed from the clinical mean for IPF patients (3.95 L) by only 1.5%. Importantly, only the heterogeneous SWIPF model reproduced the characteristic non-uniform ventilation pattern observed in CT scans of IPF patients, achieving a Normalized Root Mean Square Error (NRMSE) of 19.75% relative to the clinical data. This represented a significant improvement over the UIPF model, which had an NRMSE of 30.25%. These results demonstrate that structural heterogeneity is the key determinant of ventilation patterns in IPF and highlight mechanically vulnerable regions that could contribute to disease progression.