New hypothesis: "Six-factor theory of erythropoiesis control" HIF-PH inhibitors correct TNF-α over-induction in ESA-resistant anemia.

ESAs have made significant contributions to the treatment of renal anemia over the years. Furthermore, many reports have been published on the tissue-protective and anti-inflammatory effects of ESAs. While the normal EPO receptor is an EPOR homodimer, their tissue-protective and anti-inflammatory effects are distinct from those of ESAs, as they are primarily mediated by a heteroreceptor consisting of EPOR and CD131. Conversely, the paradox exists that large doses of ESAs may be harmful to the human body, necessitating the construction of a new theory, along with the development of ESA-resistant anemia. Incorporating the pharmacological effects of recently introduced HIF-PH inhibitors, we propose a new hypothesis, the "six-factor theory of erythropoiesis control." Because a single experimental or observational study is not sufficient to prove the theory, we present it in a review format.The six factors are EPO, Tumor Necrosis Factor-α (TNF-α), Leptin, Hypoxia-Inducible Factor （HIF）, GATA transcription factor (GATA), and Nuclear Factor-kappa B (NF-κB). The underlying cause of erythropoiesis-stimulating agent (ESA)-resistant anemia is the over-induction of TNF-α by large amounts of ESA itself. This is corrected by HIF-PH inhibitors. Iron metabolism and hemoglobin synthesis control are downstream of the six factors that regulate the baseline balance between red blood cell production and infection defense. Iron metabolism is controlled from the upstream by TNF-α and Leptin, which inhibit iron utilization, and by HIF and EPO, which promote iron utilization. Important downstream factors are Transferrin Receptor (TfR) 2, Hepcidin, Erythroferrone, and Fibroblast Growth Factor 23 (FGF23). FGF23, TfR2, and Leptin are at the crossroads of erythropoiesis, iron metabolism, and bone metabolism. Endogenous EPO is reduced by ESA overdose and restored by HIF-PH inhibitors. The pharmacological action of HIF-PH inhibitors, which are highly effective in treating ESA-resistant anemia, is to produce physiological EPO and improve iron metabolism. Furthermore, HIF-PH inhibitors adjust the imbalance of the six-factor network, creating an environment for efficient red blood cell production. The basis for this is the suppression of TNF-α production by HIF-PH inhibitors. Clinically, if sufficient iron can be replenished to protect the body from the harmful effects of iron deficiency and side effects such as thrombosis can be controlled, HIF-PH inhibitors may become the first choice of standard treatment for renal anemia. The advent of HIF-PH inhibitors has shed light on previously unknown biological mechanisms, and discussions are likely to progress on fine-tuning the treatment of renal anemia and the combined use of ESAs and HIF-PH inhibitors in small doses.