fetal hemoglobin inducer drugs can improve symptoms of -globin chain precipitation and ineffective erythropoiesis in -thalassemia , and are able to reduce hemoglobin s production in sickle cell disease ( scd ) . effective expression induction of fetal hemoglobin ( hbf ) is directly associated with improved clinical status of patients , and targeting the signaling pathways active in inducing the expression of fetal hemoglobin can result in increased level of hbf production up to effective therapeutic level , reducing the complications of disease . it has been shown that activation of these signaling pathways during erythropoiesis is mediated by interaction between erythropoietin ( epo ) and erythropoietin receptor ( epo - r ) . mitogen - activated protein kinase ( mapk ) , phosphatidyl inositol 3 kinase ( pi3k ) and jak - stat are three major signaling pathways involved in erythroid differentiation . mapk signaling pathway includes three separate signaling pathways of sapk / jnk , extracellular - regulated kinase ( erk1/2 ) and p38 mapk ( sap kinase / jun kinase ) . erk1 and erk2 play a role in proliferation of early erythroid precursors and also in differentiation of final erythroid precursors . this is while activation of sapk and p38 signaling pathways through their binding to epo receptor is more important in erythroid differentiation . activation of mapk signaling pathway and associated molecules of ras and raf-1 is done by binding of grb2 adapter molecule to epo receptor . pi3-kinase signaling pathway has been shown to play an important role in proliferation , differentiation and maturation of erythroid precursors . direct binding of p85 regulatory subunit of pi3kproteinor , indirect binding of it via an adapter protein to epo - r and activation of akt results in activation of pi3-kinase / akt signaling pathway . this signaling pathway results in increased phosphorylation and activation of transcription factors involved in normal erythropoiesis including gata-1 and foxo3a . activation of jak / stat signaling pathway mediated by epo binding to epo - r plays an important role in proliferation and differentiation of erythroid precursors . in this signaling pathway , dimerization of janus kinase 2 ( jak2 ) and epo - r autophosphorylates jak2 and creates the binding site for signaling protein . several stat ( signal tranducer and activator of transcription ) proteins play a role in erythroid differentiation by binding to dimerized jak2 and are phosphorylated and thereby activated by jak2 . in this signaling pathway , stat1 , stat3 and stat5a / b are dissociated from epo - r following phosphorylation , and are transferred to the nucleus following homodimerization or heterodimerization , increasing expression of transcription factors containing interferon  activated sequence ( gas ) . 
  in several studies , drugs such as thalidomide , pomalidomide , hydroxyurea ( hu ) , decitabine and sodium butyrate have been cited as high potential drugs in induction of hbf expression . as an immunomodulator drug , thalidomide has a high inductive effect in increasing hbf level compared with sodium butyrate . in fact , thalidomide performs its inductive effect in increasing hbf levels through activation of p38mapk signaling pathway along with reactive oxygen species ( ros ) . butyrate as a histone deacetylase ( hdac ) inhibitorcan activate p38 mapk signaling pathway and guanylatecyclase in -globin gene induction in addition to causing epigenetic changes . in addition to increasing global acetylation in h4 histone , butyrate can launch signaling pathways associated with activation of c - myc , c - myb and stat-5 in human k562 and burst - forming units - erythroid ( bfu - e ) cells , resulting in increased proliferation of erythroid precursors . thricostatin , as a hdac inhibitor , is capable of inducing -globin gene expression by phosphorylating p38mapk . as a hdac inhibitor , apicidin may increase h3 and h4 acetylation in lcr region and in the region adjacent to promoter of -globin gene by activating mapk signaling pathway in k562 cells . moreover , treatment with butyrate and trichostatin activates -globin expression by activating transcription factor-2 ( atf2 ) and cre binding protein 1 ( creb1 ) via p38 mapk signaling . they cause demethylation of -globin promoter cpgs , leading to activation of this gene to differentiate adult erythroid cells . as a cytotoxic drug , hu can increase the level of hbf and produce fetal like cells in -thalassemia and sickle cell patients following erythroid differentiation induction . hu and butyrate have been found to increase -globin expression in vivo by activating cgmp / soluble guanylate cyclase ( sgc)/pkg ( cgmp - dependent protein kinase ) pathway . this drug can also induce hbf production by inducing signaling pathways associated with increased production of camp , small gtp - binding protein and secretion associated and ras related protein ( sar ) . in addition , decitabin , 5-azacitidin , thalidomide , sodium butyrate as hypomethylating agents induce hbf production ( figure 1 ) . drugs and signaling pathways involved in -globin gene induction abbreviation : jak2 , janus kinase 2 ; stat , signal transducer and activator of transcription ; epo , erythropoietin ; p , phosphate ; gf , growth factor;pi3k , phosphoinositide 3-kinase ; akt , proline - rich akt substrate ; hdacs , histone deacetylases ; camp , cyclic amp ; pka , protein kinase a ; creb , cyclic amp - responsive element - binding protein ; atf2 , activating transcription factor ; cgmp , cyclic gmp ; pkg , cgmp - dependent protein kinase ; no , nitric oxide . thalidomide , butyrate and hydroxyurea ( hu ) modulate -globin gene expression via an upstream -globin camp response element ( g - cre ) , in addition to c - jun induction of hbf via similar pathway . butyrate , thricostatin and thalidomide activate -globin expression via reactive oxygen species ( ros ) and p38 mitogen activated protein kinase ( mapk ) signaling . in addition , hu acts via no / p38 mapk . have been shown to increase total hb level 1 - 5 g / dl above baseline . other pharmacological inducers of hbf production including epo preparation , butyrate and 5-azacitidine have been shown to increase mean total hb level by approximately 2 - 3 g / dl above baseline . decitabine increases mean hb level by 1g / dl , and is tolerated at a dose with limited cytotoxicity . it has been shown that activation of these signaling pathways during erythropoiesis is mediated by interaction between erythropoietin ( epo ) and erythropoietin receptor ( epo - r ) . mitogen - activated protein kinase ( mapk ) , phosphatidyl inositol 3 kinase ( pi3k ) and jak - stat are three major signaling pathways involved in erythroid differentiation . mapk signaling pathway includes three separate signaling pathways of sapk / jnk , extracellular - regulated kinase ( erk1/2 ) and p38 mapk ( sap kinase / jun kinase ) . erk1 and erk2 play a role in proliferation of early erythroid precursors and also in differentiation of final erythroid precursors . this is while activation of sapk and p38 signaling pathways through their binding to epo receptor is more important in erythroid differentiation . activation of mapk signaling pathway and associated molecules of ras and raf-1 is done by binding of grb2 adapter molecule to epo receptor . pi3-kinase signaling pathway has been shown to play an important role in proliferation , differentiation and maturation of erythroid precursors . direct binding of p85 regulatory subunit of pi3kproteinor , indirect binding of it via an adapter protein to epo - r and activation of akt results in activation of pi3-kinase / akt signaling pathway . this signaling pathway results in increased phosphorylation and activation of transcription factors involved in normal erythropoiesis including gata-1 and foxo3a . activation of jak / stat signaling pathway mediated by epo binding to epo - r plays an important role in proliferation and differentiation of erythroid precursors . in this signaling pathway , dimerization of janus kinase 2 ( jak2 ) and epo - r autophosphorylates jak2 and several stat ( signal tranducer and activator of transcription ) proteins play a role in erythroid differentiation by binding to dimerized jak2 and are phosphorylated and thereby activated by jak2 . in this signaling pathway , stat1 , stat3 and stat5a / b are dissociated from epo - r following phosphorylation , and are transferred to the nucleus following homodimerization or heterodimerization , increasing expression of transcription factors containing interferon  activated sequence ( gas ) . in several studies , drugs such as thalidomide , pomalidomide , hydroxyurea ( hu ) , decitabine and sodium butyrate have been cited as high potential drugs in induction of hbf expression . as an immunomodulator drug , thalidomide has a high inductive effect in increasing hbf level compared with sodium butyrate . in fact , thalidomide performs its inductive effect in increasing hbf levels through activation of p38mapk signaling pathway along with reactive oxygen species ( ros ) . butyrate as a histone deacetylase ( hdac ) inhibitorcan activate p38 mapk signaling pathway and guanylatecyclase in -globin gene induction in addition to causing epigenetic changes . in addition to increasing global acetylation in h4 histone , butyrate can launch signaling pathways associated with activation of c - myc , c - myb and stat-5 in human k562 and burst - forming units - erythroid ( bfu - e ) cells , resulting in increased proliferation of erythroid precursors . thricostatin , as a hdac inhibitor , is capable of inducing -globin gene expression by phosphorylating p38mapk . as a hdac inhibitor , apicidin may increase h3 and h4 acetylation in lcr region and in the region adjacent to promoter of -globin gene by activating mapk signaling pathway in k562 cells . moreover , treatment with butyrate and trichostatin activates -globin expression by activating transcription factor-2 ( atf2 ) and cre binding protein 1 ( creb1 ) via p38 mapk signaling . they cause demethylation of -globin promoter cpgs , leading to activation of this gene to differentiate adult erythroid cells . as a cytotoxic drug , hu can increase the level of hbf and produce fetal like cells in -thalassemia and sickle cell patients following erythroid differentiation induction . hu and butyrate have been found to increase -globin expression in vivo by activating cgmp / soluble guanylate cyclase ( sgc)/pkg ( cgmp - dependent protein kinase ) pathway . this drug can also induce hbf production by inducing signaling pathways associated with increased production of camp , small gtp - binding protein and secretion associated and ras related protein ( sar ) . in addition , decitabin , 5-azacitidin , thalidomide , sodium butyrate as hypomethylating agents induce hbf production ( figure 1 ) . drugs and signaling pathways involved in -globin gene induction abbreviation : jak2 , janus kinase 2 ; stat , signal transducer and activator of transcription ; epo , erythropoietin ; p , phosphate ; gf , growth factor;pi3k , phosphoinositide 3-kinase ; akt , proline - rich akt substrate ; hdacs , histone deacetylases ; camp , cyclic amp ; pka , protein kinase a ; creb , cyclic amp - responsive element - binding protein ; atf2 , activating transcription factor ; cgmp , cyclic gmp ; pkg , cgmp - dependent protein kinase ; no , nitric oxide . thalidomide , butyrate and hydroxyurea ( hu ) modulate -globin gene expression via an upstream -globin camp response element ( g - cre ) , in addition to c - jun induction of hbf via similar pathway . butyrate , thricostatin and thalidomide activate -globin expression via reactive oxygen species ( ros ) and p38 mitogen activated protein kinase ( mapk ) signaling . according to multiple studies , hemoglobin f inducers have been shown to increase total hb level 1 - 5 g / dl above baseline . other pharmacological inducers of hbf production including epo preparation , butyrate and 5-azacitidine have been shown to increase mean total hb level by approximately 2 - 3 g / dl above baseline . decitabine increases mean hb level by 1g / dl , and is tolerated at a dose with limited cytotoxicity . the use of drugs with a high potential to stimulate erythropoiesis appears to induce hbf expression by increasing proliferation of erythroid precursors . thus , activation of signaling pathways involved in erythroid differentiation may play an important role in increased expression of -globin gene . suppression of pi3k signaling pathway has been found to cause a 75% decrease in induction of erythroid precursors . this is while suppression p38 mapk and mtor ( mammalian target of rapamycin ) signaling pathways cause 40% and 60% reduction in erythroid precursors , respectively . since epo as a major growth factor in erythroid differentiation could enhance the expression of genes such as kit ( cd117 ) and cdh1 ( e - cadherin ) through the activation of pi3-kinase , targeting this signaling pathway seems to be effective in inducing hbf expression . treatment with epo is limited because it is associated with potential risk ; erythroid expansion can increase iron absorption and extramedullary hematopoiesis . butyrate is an effective hbf inducer but its development has been limited because of suppressive effect on erythropoiesis . dnmt inhibitors used in scd patients resistant to hu might increase the risk of cancer in long time . decitabine is not carcinogenic but its effect on hbf induction is limited . among hbf inducers , hu is a common drug used for therapeutic goals in hemoglobinopathies , but the effectiveness of this drug appears to decline with long term use . moreover , it only increases hbf in approximately half of scd patients , and is less effective in increasing hbf in -thalassemia . various other toxic effects have been attributed to it : interference with enzymes for dna synthesis , granulocytopenia , gastrointestinal and cutaneous toxicity , etc . it should be mentioned that hu can be toxic , and it can still be considered generally safe for therapeutic use by appropriate dosage and proper frequency of use .
potent induction of fetal hemoglobin ( hbf ) production results in alleviating the complications of -thalassemia and sickle cell disease ( scd ) . 
 hbf inducer agents can trigger several molecular signaling pathways critical for erythropoiesis . 
 janus kinase / signal transducer and activator of transcription ( jak / stat ) , mitogen activated protein kinas ( mapk ) and phosphoinositide 3-kinase ( pi3k ) are considered as main signaling pathways , which may play a significant role in hbf induction . 
 all these signaling pathways are triggered by erythropoietin ( epo ) as the main growth factor inducing erythroid differentiation , when it binds to its cell surface receptor , erythropoietin receptor ( epo - r ) hbf inducer agents have been shown to upregulate hbf production level by triggering certain signaling pathways . as a result , understanding the pivotal signaling pathways influencing hbf induction leads to effective upregulation of hbf . in this mini review article 
 , we try to consider the correlation between hbf inducer agents and their molecular mechanisms of -globin upregulation . 
 several studies suggest that activating p38 mapk , ras and stat5 signaling pathways result in efficient hbf induction . nevertheless , the role of other erythroid signaling pathways in hbf induction seems to be indispensible and should be emphasized .