Abstract: Roxadustat (FG-4592) is a first-in-class, orally active, small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) initially developed and approved for the treatment of renal anemia in patients with chronic kidney disease (CKD). By competitively inhibiting prolyl hydroxylase domain (PHD) enzymes, roxadustat stabilizes hypoxia-inducible factors (HIFs), thereby mimicking the body's natural physiological response to hypoxia. Recent preclinical and clinical evidence highlights that the therapeutic potential of roxadustat extends significantly beyond erythropoiesis. This review explores the emerging role of roxadustat in mitigating ischemia-reperfusion injury (IRI) and providing cardiometabolic protection. Through the upregulation of antioxidant, anti-apoptotic, and pro-angiogenic pathways, roxadustat demonstrates profound protective effects in cardiac and renal ischemic models. Furthermore, it exhibits favorable metabolic regulation, including lipid-lowering effects and protection against obesity-induced atherosclerosis. Despite these promising applications, potential risks such as vascular calcification, pulmonary arterial hypertension, and immunosuppression necessitate careful evaluation. This review synthesizes current knowledge on the pharmacological activity, molecular mechanisms, structure-activity relationships, and future perspectives of roxadustat in non-anemic diseases.
1. Introduction
Roxadustat (FG-4592) is an orally bioavailable, potent, and reversible small molecule hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) [1]. It was the first-in-class compound to achieve formal marketing authorization for the treatment of anemia in patients with later-stage chronic kidney disease (CKD), both dialysis-dependent and non-dialysis-dependent [2]. While its primary clinical application leverages the HIF pathway to stimulate endogenous erythropoietin (EPO) production and improve iron utilization, the ubiquitous nature of HIFs in cellular homeostasis has prompted extensive research into its broader pharmacological applications [1][2].
Hypoxia is a critical microenvironmental factor in the pathogenesis of numerous acute and chronic conditions. Because HIFs function as master regulators of cellular adaptation to ischemia and hypoxia, pharmacological stabilization of HIFs using roxadustat represents a promising therapeutic strategy for non-anemic conditions. Specifically, recent studies have illuminated the potential of roxadustat in protecting against ischemia-reperfusion injury (IRI) across various organs and in managing cardiometabolic disorders [1][2].
2. Pharmacological Activity
Ischemia-Reperfusion Injury (IRI) Protection: Roxadustat exhibits significant protective effects against ischemic damage. In the cardiovascular system, pharmacological preconditioning with roxadustat induces ischemic tolerance by switching myocardial metabolism from aerobic to anaerobic respiration. In murine cardiac I/R models, this metabolic shift significantly reduced the infarct area, decreased plasma creatinine kinase activity, and lowered the percentage of apoptotic (TUNEL-positive) cardiomyocytes [2]. In the kidneys, roxadustat pretreatment attenuates renal IRI by suppressing inflammatory responses—evidenced by decreased macrophage infiltration and downregulated inflammatory cytokines—and by mitigating mitochondrial damage, which helps prevent the transition from acute kidney injury (AKI) to CKD [1][2].
Cardiometabolic Protection: Roxadustat demonstrates favorable regulatory effects on lipid metabolism. Clinical and preclinical observations indicate that it lowers total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides, while increasing the ratio of high-density lipoprotein (HDL) to LDL [1]. Furthermore, roxadustat protects against obesity-induced atherosclerosis. In animal models, it stabilizes adipose HIF-2α, which intensifies alkaline ceramidase 2 (ACER2)-triggered ceramide catabolism, thereby reducing atherogenic mediators [2]. Additionally, roxadustat has been shown to ameliorate macrophage inflammasome activation, protecting against insulin resistance, obesity symptoms, and liver steatosis [2].
3. Molecular Mechanism of Action
The primary mechanism of action of roxadustat involves the competitive inhibition of prolyl hydroxylase domain (PHD) enzymes (specifically PHD1, PHD2, and PHD3) [1]. Under normoxic conditions, PHDs hydroxylate the oxygen-sensitive HIF-α subunit, which is subsequently recognized by the von Hippel-Lindau (VHL) tumor suppressor protein, leading to its ubiquitination and proteasomal degradation [1]. By inhibiting PHD activity, roxadustat prevents this degradation, allowing HIF-α to accumulate, translocate into the nucleus, and dimerize with the constitutively expressed HIF-β subunit. This complex binds to hypoxia response elements (HREs) to activate the transcription of a wide array of target genes [1].
In the context of IRI and cardiometabolic protection, this transcriptional activation triggers several downstream pathways. Roxadustat upregulates vascular endothelial growth factor (VEGF) and its receptors, promoting angiogenesis and the normalization of blood flow [1]. It also exerts potent anti-oxidative and anti-apoptotic effects by upregulating target genes such as superoxide dismutase 2 (SOD2), B-cell lymphoma-2 (Bcl-2), and heme oxygenase-1 (HO-1), while activating the Akt/GSK-3β/Nrf2 pathway to inhibit ferroptosis and oxidative stress [1][2]. Furthermore, HIF stabilization shifts cellular metabolism from oxidative phosphorylation to glycolysis, which alters the redox potential and reduces the generation of mitochondrial reactive oxygen species (ROS) [1].
4. Structure-Activity Relationship (SAR)
Roxadustat is a small molecule with the chemical formula C19H16N2O5 and a molecular weight of 352.34 g/mol [1]. It is classified as a second-generation HIF-PHI. Structurally, it was synthesized by adding a phenoxy group to carbon-7 of the quinoline core of its precursor molecule, FG-2261 [1]. This structural modification significantly enhanced its pharmacokinetic profile and potency.
The molecule is specifically designed to mimic the binding mode of 2-oxoglutarate (α-ketoglutarate), which is a necessary co-substrate for the catalytic activity of PHD enzymes [1][4]. By competing with 2-oxoglutarate for the active site of the HIF-PHD enzymes, roxadustat effectively blocks the hydroxylation of the highly conserved proline residues on the HIF-α subunit, thereby tricking the cell into mounting orchestrated survival and repair responses typically reserved for hypoxic environments [4].
5. Current Limitations
Despite its broad therapeutic potential, the clinical application of roxadustat is accompanied by several limitations and potential adverse effects. One major concern is the risk of vascular calcification. Prolonged HIF activation, acting synergistically with phosphate, can promote the osteogenic transdifferentiation and calcification of vascular smooth muscle cells, potentially increasing cardiovascular risks in CKD patients [1]. Additionally, clinical case reports have raised concerns about the potential for roxadustat to induce or exacerbate pulmonary arterial hypertension (PAH) [1][5].
Metabolically, while roxadustat generally improves lipid profiles, some studies indicate that HIF-1α upregulation can shift metabolism in ways that reduce fatty acid oxidation, leading to lipid accumulation and the overproduction of lactic acid. This resulting acidosis can trigger the release of intracellular potassium ions, explaining the hyperkalemia observed in some patients [1][3]. Finally, roxadustat may exert immunosuppressive effects; clinical trials have noted a higher incidence of urinary tract infections and pneumonia in roxadustat-treated groups compared to placebo, suggesting a complex interaction with inflammatory and immune responses [1].
6. Future Perspectives
The pleiotropic nature of HIF stabilization presents both significant opportunities and challenges for the future of roxadustat. Because HIF targets a vast network of genes involved in diverse physiological processes, further research is imperative to delineate the delicate balance between its protective effects (e.g., ischemic tolerance, angiogenesis, metabolic correction) and its deleterious effects (e.g., fibrosis, vascular calcification, immunosuppression) [1][2].
Future clinical trials must focus on long-term cardiovascular safety and the monitoring of off-target effects in non-anemic populations. Additionally, exploring optimized administration strategies—such as short-term preconditioning prior to organ transplantation, localized delivery for wound healing, or intermittent dosing regimens—could maximize the cardiometabolic and ischemic benefits of roxadustat while minimizing systemic adverse events [2]. As our understanding of oxygen-sensing mechanisms deepens, roxadustat may pave the way for novel therapeutic paradigms in ischemic heart disease, acute kidney injury, and metabolic syndrome.
