Decoding the complexity: mechanistic insights into comorbidities in idiopathic pulmonary fibrosis

The complex pathogenic relationships between idiopathic pulmonary fibrosis (IPF) and its usually associated comorbidities remain poorly understood. While evidence suggests that some comorbidities may directly influence the development or progression of IPF, or vice versa, whether these associations are causal or arise independently due to shared risk factors, such as ageing, smoking, lifestyle and genetic susceptibility, is still uncertain. Some comorbidities, such as metabolic syndromes, gastro-oesophageal reflux disease and obstructive sleep apnoea, precede the development of IPF. In contrast, others, such as pulmonary hypertension and lung cancer, often become apparent after IPF onset or during its progression. These timing patterns suggest a directional relationship in their associations. The issue is further complicated by the fact that patients often have multiple comorbidities, which may interact and exacerbate one another, creating a vicious cycle. To clarify these correlations, some studies have used causal inference methods (e.g. Mendelian randomisation) and exploration of underlying mechanisms; however, these efforts have not yet generated conclusive insights. In this review, we provide a general overview of the relationship between IPF and its comorbidities, emphasising the pathogenic mechanisms underlying each comorbidity, potential shared pathobiology with IPF and, when available, causal insights from Mendelian randomisation studies.