# JAK-STAT signaling: molecular mechanism and targeted treatment in dento-maxillofacial abnormalities **Authors:** Zihan Huang, Yiwen Cui, Wenyi Zhang, Jiachen Shen, Qinggang Dai, Siyuan Sun, Lingyong Jiang PMC · DOI: 10.1038/s41368-025-00399-z · 2026-03-05 ## TL;DR This review explores how JAK-STAT signaling influences dento-maxillofacial development and how targeting this pathway could lead to new treatments for related abnormalities. ## Contribution The paper provides a comprehensive review of JAK-STAT signaling's role in dento-maxillofacial development and its potential as a therapeutic target. ## Key findings - JAK-STAT signaling regulates key processes in dentofacial development, including ossification and enamel formation. - Mutations in JAK-STAT signaling are linked to syndromes with severe dento-maxillofacial abnormalities. - Drugs like baricitinib and imatinib show promise in treating skeletal disorders related to JAK-STAT dysfunction. ## Abstract Dento-maxillofacial abnormalities are highly prevalent and arise as a result of a variety of etiological factors, presenting substantial challenges to treatment. The JAK-STAT signaling plays a pivotal role in dentofacial development, regulating endochondral ossification, intramembranous ossification, dental follicle formation, and enamel development. Mutations in the JAK-STAT signaling lead to syndromes associated with severe dento-maxillofacial abnormalities, including Growth Hormone Insensitivity Syndrome and Autosomal Dominant Hyper-IgE Syndrome. Corresponding mouse disease models have been developed to simulate the phenotypes observed in clinical patients and investigate their underlying mechanism. Meanwhile, several medications targeting JAK-STAT signaling, including baricitinib and imatinib, have been developed for clinical application, demonstrating significant effects in skeletal disorders such as osteoporosis and osteoarthritis, indicating promising effects in development and abnormalities of dento-maxillofacial. In this review, we aim to summarize the role of JAK-STAT signaling in the development and abnormalities of dento-maxillofacial bone, and the relevant molecules that may be utilized for clinical treatment, to shed new light on the precise treatment of dento-maxillofacial abnormalities. ## Linked entities - **Chemicals:** baricitinib (PubChem CID 44205240), imatinib (PubChem CID 5291) - **Diseases:** Growth Hormone Insensitivity Syndrome (MONDO:0015892), Autosomal Dominant Hyper-IgE Syndrome (MONDO:0007818), osteoporosis (MONDO:0005298), osteoarthritis (MONDO:0005178) ## Full-text entities - **Genes:** Csf3 (colony stimulating factor 3 (granulocyte)) [NCBI Gene 12985] {aka Csfg, G-CSF, MGI-IG}, Cdh5 (cadherin 5) [NCBI Gene 12562] {aka 7B4, Cd144, VE-Cad, VECD, VEcad, Vec}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, STAT3 (signal transducer and activator of transcription 3) [NCBI Gene 6774] {aka ADMIO, ADMIO1, APRF, HIES}, STAT4 (signal transducer and activator of transcription 4) [NCBI Gene 6775] {aka DPMC, SLEB11}, MIR224 (microRNA 224) [NCBI Gene 407009] {aka MIRN224, miRNA224}, Stat6 (signal transducer and activator of transcription 6) [NCBI Gene 20852], Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, RAC1 (Rac family small GTPase 1) [NCBI Gene 5879] {aka MIG5, MRD48, Rac-1, TC-25, p21-Rac1}, Socs3 (suppressor of cytokine signaling 3) [NCBI Gene 12702] {aka Cis3, Cish3, EF-10, Ef10, SSI-3, Ssi3}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 22339] {aka L-VEGF, Vegf, Vpf}, Rock1 (Rho-associated coiled-coil containing protein kinase 1) [NCBI Gene 19877] {aka 1110055K06Rik, Rock-I}, Prrx1 (paired related homeobox 1) [NCBI Gene 18933] {aka A230024N07Rik, K-2, MHox1, Pmx, Pmx1, Prx1}, STAT6 (signal transducer and activator of transcription 6) [NCBI Gene 6778] {aka D12S1644, HIES6, IL-4-STAT, STAT6B, STAT6C}, Pias2 (protein inhibitor of activated STAT 2) [NCBI Gene 17344] {aka ARIP3, DIP, Dib, Miz1, PIASxalpha, PIASxalpha6}, Sp7 (Sp7 transcription factor 7) [NCBI Gene 170574] {aka 6430578P22Rik, C22, Osx}, Ccnd1 (cyclin D1) [NCBI Gene 12443] {aka CycD1, Cyl-1, PRAD1, bcl-1, cD1}, Il13 (interleukin 13) [NCBI Gene 16163] {aka Il-13}, Dusp2 (dual specificity phosphatase 2) [NCBI Gene 13537] {aka PAC1}, Tyk2 (tyrosine kinase 2) [NCBI Gene 54721] {aka JTK1}, Pts (6-pyruvoyl-tetrahydropterin synthase) [NCBI Gene 19286] {aka PTPS}, Mmp3 (matrix metallopeptidase 3) [NCBI Gene 17392] {aka EMS-2, MMP-3, SL-1, SLN-1, SLN1, STR-1}, Stat1 (signal transducer and activator of transcription 1) [NCBI Gene 20846] {aka 2010005J02Rik}, Kdr (kinase insert domain protein receptor) [NCBI Gene 16542] {aka 6130401C07, Flk-1, Flk1, Krd-1, Ly73, VEGFR-2}, Atf3 (activating transcription factor 3) [NCBI Gene 11910] {aka LRG-21}, Mir338 (microRNA 338) [NCBI Gene 723844] {aka Mirn338, mir-338, mmu-mir-338}, Il2ra (interleukin 2 receptor, alpha chain) [NCBI Gene 16184] {aka CD25, Il2r, Ly-43}, Epas1 (endothelial PAS domain protein 1) [NCBI Gene 13819] {aka HIF-2alpha, HIF2A, HLF, HRF, MOP2, bHLHe73}, Tfrc (transferrin receptor) [NCBI Gene 22042] {aka 2610028K12Rik, CD71, E430033M20Rik, Mtvr1, TFR, TFR1}, Fos (Fos proto-oncogene, AP-1 transcription factor subunit) [NCBI Gene 14281] {aka D12Rfj1, c-fos, cFos}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, SP7 (Sp7 transcription factor) [NCBI Gene 121340] {aka OI11, OI12, OSX, osterix}, Ambn (ameloblastin) [NCBI Gene 11698], Ptpn11 (protein tyrosine phosphatase, non-receptor type 11) [NCBI Gene 19247] {aka 2700084A17Rik, PTP1D, PTP2C, SAP-2, SH-PTP2, SH-PTP3}, Ifnb1 (interferon beta 1, fibroblast) [NCBI Gene 15977] {aka IFN-beta, IFNB, If1da1, Ifb}, Tnfrsf11b (tumor necrosis factor receptor superfamily, member 11b (osteoprotegerin)) [NCBI Gene 18383] {aka OCIF, Opg, TR1}, Il6ra (interleukin 6 receptor, alpha) [NCBI Gene 16194] {aka CD126, IL-6R, IL-6R-alpha, IL-6RA, Il6r}, STAT5B (signal transducer and activator of transcription 5B) [NCBI Gene 6777] {aka GHISID2, STAT5}, Lep (leptin) [NCBI Gene 16846] {aka ob, obese}, Stat2 (signal transducer and activator of transcription 2) [NCBI Gene 20847] {aka 1600010G07Rik}, Pias1 (protein inhibitor of activated STAT 1) [NCBI Gene 56469] {aka 2900068C24Rik, Ddxbp1, GBP}, Stat5a (signal transducer and activator of transcription 5A) [NCBI Gene 20850] {aka STAT5}, Stat4 (signal transducer and activator of transcription 4) [NCBI Gene 20849], Cish (cytokine inducible SH2-containing protein) [NCBI Gene 12700] {aka CIS-1, CIS1, Cis, F17, F23, SOCS}, CASP3 (caspase 3) [NCBI Gene 836] {aka CPP32, CPP32B, SCA-1}, Klk4 (kallikrein related-peptidase 4 (prostase, enamel matrix, prostate)) [NCBI Gene 56640] {aka ESMP1, KLK-L1, PSTS, Prss17}, STAT1 (signal transducer and activator of transcription 1) [NCBI Gene 6772] {aka CANDF7, IMD31A, IMD31B, IMD31C, ISGF-3, STAT91}, Cntfr (ciliary neurotrophic factor receptor) [NCBI Gene 12804] {aka Cntfralpha}, Gsk3b (glycogen synthase kinase 3 beta) [NCBI Gene 56637] {aka 7330414F15Rik, 8430431H08Rik, GSK-3, GSK-3beta, GSK3}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, Mlip (muscular LMNA-interacting protein) [NCBI Gene 69642] {aka 2310046A06Rik, CIP}, Cd4 (CD4 antigen) [NCBI Gene 12504] {aka L3T4, Ly-4}, alp (alopecia, recessive) [NCBI Gene 11691], Nfatc1 (nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1) [NCBI Gene 18018] {aka 2210017P03Rik, NF-ATc, NFAT2, NFATc, Nfatcb}, Il27 (interleukin 27) [NCBI Gene 246779] {aka IL-27, IL-27-A, IL-27p28, IL27-A, Il30, p28}, Sh2b3 (SH2B adaptor protein 3) [NCBI Gene 16923] {aka Lnk}, Ephb2 (Eph receptor B2) [NCBI Gene 13844] {aka Cek5, Drt, ETECK, Erk, Hek5, Nuk}, Dusp1 (dual specificity phosphatase 1) [NCBI Gene 19252] {aka 3CH134, MKP1, Ptpn16, erp, mkp-1}, Thpo (thrombopoietin) [NCBI Gene 21832] {aka Mgdf, Ml, Mpllg, Tpo}, Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha} - **Diseases:** enamel hypoplasia (MESH:D003744), bone fractures (MESH:D050723), growth retardation (MESH:D006130), pulmonary infections (MESH:D012141), periodontitis (MESH:D010518), inflammation (MESH:D007249), JAK (MESH:C564858), dentoalveolar complex abnormalities (MESH:D010509), avascular necrosis of the femoral head (MESH:D005271), osteoporotic (MESH:D058866), eosinophilia (MESH:D004802), polycythemia vera (MESH:D011087), Paget's disease of bone (MESH:D010001), skeletal disorders (MESH:C564967), dysmorphic (MESH:D057215), diabetes (MESH:D003920), malignancies (MESH:D009369), long bone arthritis (MESH:D050398), mandibular fractures (MESH:D008337), Erythrocytosis (MESH:D011086), dermatitis (MESH:D003872), bone resorption (MESH:D001862), chronic eosinophilic leukemia (MESH:C580364), STAT abnormalities (MESH:C566796), bone marrow fibrosis (MESH:D055728), microcephaly (MESH:D008831), tumorigenesis (MESH:D063646), enamel defects (MESH:D000094602), impaired erythropoiesis (MESH:C563479), complex (MESH:D048090), musculoskeletal abnormalities (MESH:D009139), malalignment (MESH:D017760), oral disease (MESH:D009059), high-arched palate (MESH:D007569), hypoxic (MESH:D002534), facial malformation (MESH:C565579), femoral condyle injury (MESH:D000092443), temporomandibular joint disorders (MESH:D013705), periprosthetic osteolysis (MESH:D057068), cranial deformities (MESH:D003389), cartilage loss (MESH:D002357), craniosynostosis (MESH:D003398), hypermobility (MESH:C536196), autoinflammatory conditions (MESH:D056660), Dento-maxillofacial abnormalities (MESH:D019767), osteoarthritis (MESH:D010003), craniofacial dysmorphia (MESH:C537340), craniofacial deformities (MESH:D005157), primary immunodeficiency disorder (MESH:D000081207), Hch (MESH:C562937), AgP (MESH:D010520), Immunodeficiency 31 C (OMIM:211750), death (MESH:D003643), malocclusion (MESH:D008310), eczema (MESH:D004485), viral infections (MESH:D014777), craniomaxillofacial bones (MESH:D000077275), anemia (MESH:D000740), Growth Hormone Insensitivity Syndrome (MESH:D046150), myeloproliferative disorders (MESH:D009196) - **Chemicals:** phosphate (MESH:D010710), AG490 (MESH:C095512), Tofacitinib (MESH:C479163), Fucoidan (MESH:C007789), nickel (MESH:D009532), Imatinib (MESH:D000068877), iron (MESH:D007501), prostaglandin E2 (MESH:D015232), fludarabine (MESH:C024352), tyrosine (MESH:D014443), Metformin (MESH:D008687), Ruxolitinib (MESH:C540383), trans-fatty acids (MESH:D044242), blood glucose (MESH:D001786), Resveratrol (MESH:D000077185), polyunsaturated fatty acids (MESH:D005231), glycosaminoglycan (MESH:D006025), 2,3,5,4'-tetrahydroxystilbene-2-O-beta-glucoside (-), hydrogen sulfide (MESH:D006862), nicotine (MESH:D009538), fatty acids (MESH:D005227), titanium (MESH:D014025), lipopolysaccharide (MESH:D008070), WKYMVm (MESH:C113617), ATP (MESH:D000255), SHR0302 (MESH:C000615713), steroid (MESH:D013256), Eugenol (MESH:D005054), Eupatilin (MESH:C045325), ROS (MESH:D017382), Baricitinib (MESH:C000596027), 1,25-dihydroxyvitamin D3 (MESH:D002117), GLPG0634 (MESH:C584571), Fedratinib (MESH:C528327) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116], Staphylococcus aureus (species) [taxon 1280], Humulus japonicus (Japanese hop, species) [taxon 3485] - **Mutations:** G > A, p.Ser466Arg, R96C, JAK2 V617F, S645P, H595D, V617F - **Cell lines:** RAW264.7 — Mus musculus (Mouse), Mouse leukemia, Cancer cell line (CVCL_0493), HERS — Capra hircus (Goat), Finite cell line (CVCL_IR22), MLO-Y4 — Mus musculus (Mouse), Transformed cell line (CVCL_M098) ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12960723/full.md --- Source: https://tomesphere.com/paper/PMC12960723