Roxadustat for SARS-CoV-2 Infection: Old Signaling Raised New Hopes

Roxadustat (RXT) (4-hydroxyl-1-methyl-7-phenoxyisoquinoline-3-caboxylic acid) (Fig. 1) is an orally active prolyl hydroxylase (PHD) inhibitor that increases production of endogenous erythropoietin with subsequent activation of bone marrow to produce red blood cells [1]. RXT is indicated in the management of anemia in chronic kidney disease (CKD) [1]. RXT was approved in China and Japan in 2018 and 2019, respectively, for the treatment of CKD-induced anemia [1]. RXT was approved by the European Union in 2021 for the treatment of anemia caused by CKD [2]. RXT has high bioavailability, high plasma protein binding, and is metabolized by P450 and excreted in the urine. RXT maximum plasma concentration is reached within 1 h. However, RXT bioavailability and plasma concentration are reduced by phosphate binders, which are commonly prescribed in patients with CKD to treat hyperphosphatemia [16]. PHD is responsible for the inactivation of hypoxiainducible factor HIF-1α under normoxic conditions; however, under hypoxic conditions PHD is inhibited and HIF-1α is stabilized, activated, and transcriptionally energetic [3]. HIF-1α could be a protective mechanism against the pathogenesis of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection. HIF-1α inhibits the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protein protease 2 (TMPRSS2), which