Insights into HIF Prolyl Hydroxylase Inhibitors: Recent Advances and Expanding Therapeutic Applications beyond Anemia

Abstract

Abstract Oxygen homeostasis is fundamental to cellular and organismal physiology and is primarily governed by the hypoxia-inducible factor (HIF) signaling pathway. Within this pathway, prolyl hydroxylase domain enzymes (PHDs) serve as a key oxygen sensor that regulates HIF-α stability and thus controls hypoxic transcriptional responses. Dysregulation of this system is implicated in a broad spectrum of hypoxia-related diseases, making PHDs an important class of therapeutic targets. This perspective summarizes recent advances in PHD inhibitors, with emphasis on structural and functional differences among PHD isoforms and the predominance of PHD2 in drug discovery. We review key screening and design strategies for both carboxylate and non-carboxylate chemotypes. Current clinical progress and major challenges, such as isoform selectivity, safety concerns, and pharmacokinetic limitations, are discussed. Finally, we highlight emerging therapeutic opportunities beyond anemia, including ischemic, metabolic, and inflammatory diseases, providing a framework for precision targeting of oxygen-sensing pathways.