Addressing Complexity in Pulmonary Hypertension The FoxO1 Case

Pulmonary arterial hypertension (PAH) is a mysterious killer that, like cancer, is characterized by tremendous complexity. A myriad of apparently unrelated molecular abnormalities have been described but, perhaps because of this complexity, the progress in PAH drug development suffers from poor bench-to-bedside translation.(1) Savai et al,(2) attacked the master transcription factor forkhead box O1 (FoxO1), arguing that targeting more proximal hubs that integrate many mechanisms in the PAH pathogenesis cascade will be more effective than attacking individual distal targets. It is not the first time that this has been attempted in PAH. Master transcription factors like nuclear factor of activated T-cell c2 (NFATc2),(3) hypoxia inducible factor 1 alpha (HIF-1 alpha),(4) and signal transducer and activator of transcription 3 (STAT3)(5) have effectively been targeted in PAH models. Attempts to integrate this fragmented field, like the metabolic(6) and inflammatory(7) theories of PAH, have emerged.