Roxadustat beyond anemia: A review of its pleiotropic mechanisms and translational potential

Roxadustat, a first-in-class oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), has been approved for the clinical management of anemia secondary to chronic kidney disease (CKD). Previously published reviews generally focus on single-organ or individual disease manifestations, and a comprehensive systematic overview regarding its potential indications across multiple organ systems remains lacking. Beyond stimulating erythropoiesis, roxadustat triggers extensive transcriptional cascades via systemic stabilization of hypoxia-inducible factor (HIF), thereby exerting pleiotropic pharmacological actions throughout diverse organs. Accumulating preclinical findings and emerging clinical data verify that roxadustat facilitates cardiovascular injury repair, confers neuroprotection, remodels systemic metabolism, maintains iron homeostasis and modulates the tumor microenvironment, conferring promising translational prospects for repurposing in various non-anemic disorders. Nevertheless, widespread activation of the HIF signaling pathway is accompanied by safety concerns including tumor progression promotion, adverse vascular events and endocrine dysfunctions. From a multisystem perspective, this review systematically integrates the molecular mechanisms, preclinical outcomes and translational evidence of roxadustat to fill the existing gaps in available literature. We further highlight that precise patient stratification and standardized long-term safety surveillance are indispensable to fully exploit the therapeutic potential of roxadustat beyond anemia treatment.