Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: Mechanisms, Therapeutic Applications, and Developmental Progress

Rationale & Objective This review aims to synthesize the clinical translation landscape of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs), evaluating both their therapeutic potential and the practical challenges that affect their use in the management of chronic kidney disease (CKD)-related anemia. Study Design Narrative review integrating findings from scientific literature and clinical trial data on HIF-PHIs. Setting & Participants The analysis includes agents approved for CKD-related anemia, those in ongoing clinical development, and candidates discontinued during trials. Exposure(s) The primary focus is HIF-PHIs, which stabilize HIF-α subunits and modulate the expression of downstream genes involved in erythropoiesis, iron metabolism, and other processes. Outcome(s) Key outcomes for each HIF-PHI include pharmacological characteristics, hemoglobin-raising efficacy, safety profiles, developmental status, and challenges encountered. Analytical Approach Qualitative analysis comparing and contrasting the properties, clinical progress, and lessons learned from different HIF-PHIs. Results The review summarizes currently approved HIF-PHIs, highlights promising agents in clinical development, and examines compounds that have been discontinued. It further analyzes the divergence between hemoglobin-raising efficacy and safety signals that have shaped regulatory decisions and influenced clinical guideline recommendations. Limitations As a narrative review, the conclusions are based on published data, may be subject to selection bias. In addition, limited or unpublished data, particularly for early-stage or discontinued agents, constrains the comprehensiveness of the analysis. Conclusions HIF-PHI represents a major therapeutic advancement, particularly for renal anemia. This review consolidates current knowledge, evaluates advantages alongside emerging safety concerns, and discusses the evolving role of HIF-PHIs in clinical practice guidelines.