{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T22:57:34Z","timestamp":1792364254991,"version":"4.4.0"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,22]],"date-time":"2026-03-22T00:00:00Z","timestamp":1774137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2-Year Research Grant from Pusan National University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neurofibromatosis type 1 (NF1) and NF2-related schwannomatosis (NF2-SWN) are major genetic tumor predisposition syndromes characterized by progressive, often debilitating neoplasms of the peripheral and central nervous systems. Over the past five years, substantial advances in molecular genetics, signaling biology, and targeted therapeutic development have reshaped diagnostic and management paradigms for both disorders. This Perspective synthesizes recent developments, including gene-based reclassification, emergence of MEK inhibitor therapy in NF1, renewed evaluation of bevacizumab and kinase-pathway inhibitor brigatinib, the discovery of a novel T\u03b2R1-RKIP pathogenic axis, and a brain-penetrant HDAC inhibitor in NF2-SWN. These insights highlight a shift toward precision-medicine strategies and mechanistically driven therapies poised to redefine future clinical care.<\/jats:p>","DOI":"10.3390\/ijms27062867","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:48:42Z","timestamp":1774259322000},"page":"2867","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Emerging Molecular Insights and Therapeutic Directions in Neurofibromatosis Type 1 and NF2-Related Schwannomatosis"],"prefix":"10.3390","volume":"27","author":[{"given":"Soyoung","family":"Park","sequence":"first","affiliation":[{"name":"Institute of Rare Genetic Disease, PRG S&Tech Co., Ltd., Busan 46274, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Gyun","family":"Woo","sequence":"additional","affiliation":[{"name":"Institute of Rare Genetic Disease, PRG S&Tech Co., Ltd., Busan 46274, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-mi","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea"},{"name":"Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6866-7248","authenticated-orcid":false,"given":"Bae-Hoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Institute of Rare Genetic Disease, PRG S&Tech Co., Ltd., Busan 46274, Republic of Korea"},{"name":"Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6037-7219","authenticated-orcid":false,"given":"Bum-Joon","family":"Park","sequence":"additional","affiliation":[{"name":"Institute of Rare Genetic Disease, PRG S&Tech Co., Ltd., Busan 46274, Republic of Korea"},{"name":"Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 46241, Republic of Korea"},{"name":"Institute of Systems Biology, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17004","DOI":"10.1038\/nrdp.2017.4","article-title":"Neurofibromatosis type 1","volume":"3","author":"Gutmann","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9658","DOI":"10.1073\/pnas.88.21.9658","article-title":"Identification of the neurofibromatosis type 1 gene product","volume":"88","author":"Gutmann","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.1016\/S0140-6736(09)60259-2","article-title":"Neurofibromatosis type 2","volume":"373","author":"Asthagiri","year":"2009","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1634\/theoncologist.2012-0162","article-title":"Clinical features of schwannomatosis: A retrospective analysis of 87 patients","volume":"17","author":"Merker","year":"2012","journal-title":"Oncologist"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1038\/s41436-021-01170-5","article-title":"Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: An international consensus recommendation","volume":"23","author":"Legius","year":"2021","journal-title":"Genet. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1016\/j.gim.2022.05.007","article-title":"Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: An international consensus recommendation","volume":"24","author":"Plotkin","year":"2022","journal-title":"Genet. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1002\/ajmg.a.63346","article-title":"Neurofibromatosis- and schwannomatosis-associated tumors: Approaches to genetic testing and counseling considerations","volume":"191","author":"Radtke","year":"2023","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12935-023-02940-8","article-title":"The genetic landscape and possible therapeutics of neurofibromatosis type 2","volume":"23","author":"Ghalavand","year":"2023","journal-title":"Cancer Cell Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/s41698-025-01078-2","article-title":"Natural history of SPP1 signaling in NF1 tumors","volume":"9","author":"Njoya","year":"2025","journal-title":"npj Precis. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1007\/s11912-024-01527-4","article-title":"Past, Present, and Future Therapeutic Strategies for NF-1-Associated Tumors","volume":"26","author":"Na","year":"2024","journal-title":"Curr. Oncol. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1038\/s41467-023-37226-0","article-title":"Cellular mechanisms of heterogeneity in NF2-mutant schwannoma","volume":"14","author":"Zhang","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e192658","DOI":"10.1172\/jci.insight.192658","article-title":"Tumor heterogeneity underlies clinical outcome and MEK inhibitor response in somatic NF1-mutant glioblastoma","volume":"10","author":"Pan","year":"2025","journal-title":"JCI Insight"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1056\/NEJMoa1912735","article-title":"Selumetinib in children with inoperable plexiform neurofibromas","volume":"382","author":"Gross","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_14","unstructured":"(2025, February 11). FDA Approves Mirdametinib for Adult and Pediatric Patients with Neurofibromatosis Type 1 Who Have Symptomatic Plexiform Neurofibromas Not Amenable to Complete Resection, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-approves-mirdametinib-adult-and-pediatric-patients-neurofibromatosis-type-1-who-have-symptomatic."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1016\/S0140-6736(25)00986-9","article-title":"Efficacy and safety of selumetinib in adults with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas (KOMET): A multicentre, international, randomised, placebo-controlled, parallel, double-blind, phase 3 study","volume":"405","author":"Chen","year":"2025","journal-title":"Lancet"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Imataka, G., Kuwashima, S., Hayashi, S., Ogino, K., Hoshiyama, E., Naruse, K., and Shiraishi, H. (2025). Neurofibromatosis Type 1 and MEK Inhibition: A Comprehensive Review with Focus on Selumetinib Therapy. J. Clin. Med., 14.","DOI":"10.20944\/preprints202506.0639.v1"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e54","DOI":"10.1158\/1078-0432.CCR-17-0590","article-title":"Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 2 and Related Disorders","volume":"23","author":"Evans","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1200\/JCO.2015.64.3817","article-title":"Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting from Neurofibromatosis Type 2-Associated Vestibular Schwannomas","volume":"34","author":"Blakeley","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Chang, L.S., Oblinger, J.L., Smith, A.E., Ferrer, M., Angus, S.P., Hawley, E., Petrilli, A.M., Beauchamp, R.L., Riecken, L.B., and Erdin, S. (2021). Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0252048"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1056\/NEJMoa0902579","article-title":"Hearing improvement after bevacizumab in patients with neurofibromatosis type 2","volume":"361","author":"Plotkin","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_21","unstructured":"(2026, January 12). Innovative Trial for Understanding the Impact of Targeted Therapies in NF2-Related Schwannomatosis (INTUITT-NF2), Available online: https:\/\/clinicaltrials.gov\/study\/NCT04374305."},{"key":"ref_22","first-page":"vdad099","article-title":"A systematic review of targeted therapy for vestibular schwannoma in patients with NF2-related schwannomatosis","volume":"5","author":"Chiranth","year":"2023","journal-title":"Neurooncol. Adv."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kim, B.H., Chung, Y.H., Woo, T.G., Kang, S.M., Park, S., Kim, M., and Park, B.J. (2024). NF2-Related Schwannomatosis (NF2): Molecular Insights and Therapeutic Avenues. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202405.0384.v1"},{"key":"ref_24","first-page":"1","article-title":"Deep Response to Anti-PD-1 Therapy of Metastatic Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumor with CD274\/PD-L1 Amplification","volume":"3","author":"Bohanes","year":"2019","journal-title":"JCO Precis. Oncol."},{"key":"ref_25","first-page":"281","article-title":"Bevacizumab in neurofibromatosis type 2 (NF2) related vestibular schwannomas: A nationally coordinated approach to delivery and prospective evaluation","volume":"3","author":"Morris","year":"2016","journal-title":"Neurooncol. Pract."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s00280-014-2456-2","article-title":"Long-term toxicity of bevacizumab therapy in neurofibromatosis 2 patients","volume":"73","author":"Slusarz","year":"2014","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1093\/neuonc\/noad066","article-title":"Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma","volume":"25","author":"Plotkin","year":"2023","journal-title":"Neuro Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.tranon.2019.04.022","article-title":"Limitations of Anti-Angiogenic Treatment of Tumors","volume":"12","author":"Ribatti","year":"2019","journal-title":"Transl. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41698-024-00627-5","article-title":"NF2: An underestimated player in cancer metabolic reprogramming and tumor immunity","volume":"8","author":"Xu","year":"2024","journal-title":"npj Precis. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e23809","DOI":"10.1096\/fj.202400019RR","article-title":"The molecular biology of NF2\/Merlin on tumorigenesis and development","volume":"38","author":"Vlashi","year":"2024","journal-title":"FASEB J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1056\/NEJMoa2400985","article-title":"Brigatinib in NF2-Related Schwannomatosis with Progressive Tumors","volume":"390","author":"Plotkin","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1158\/1535-7163.MCT-17-1210","article-title":"Loss of NF2 Induces TGF\u03b2 Receptor 1-mediated Noncanonical and Oncogenic TGF\u03b2 Signaling: Implication of the Therapeutic Effect of TGF\u03b2 Receptor 1 Inhibitor on NF2 Syndrome","volume":"17","author":"Cho","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10073","DOI":"10.18632\/oncotarget.3543","article-title":"NF2 blocks Snail-mediated p53 suppression in mesothelioma","volume":"6","author":"Cho","year":"2015","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1158\/1541-7786.MCR-21-0373","article-title":"RKIP Induction Promotes Tumor Differentiation via SOX2 Degradation in NF2-Deficient Conditions","volume":"20","author":"Cho","year":"2022","journal-title":"Mol. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1093\/neuonc\/noae282","article-title":"Therapeutic effect of novel drug candidate, PRG-N-01, on NF2 syndrome-related tumor","volume":"27","author":"Chung","year":"2025","journal-title":"Neuro Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1093\/neuonc\/nor072","article-title":"AR42, a novel histone deacetylase inhibitor, as a potential therapy for vestibular schwannomas and meningiomas","volume":"13","author":"Bush","year":"2011","journal-title":"Neuro Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/lary.22392","article-title":"Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas","volume":"122","author":"Jacob","year":"2012","journal-title":"Laryngoscope"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lucas, D.M., Alinari, L., West, D.A., Davis, M.E., Edwards, R.B., Johnson, A.J., Blum, K.A., Hofmeister, C.C., Freitas, M.A., and Parthun, M.R. (2010). The novel deacetylase inhibitor AR-42 demonstrates pre-clinical activity in B-cell malignancies In Vitro and In Vivo. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010941"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/ijc.25660","article-title":"The novel histone deacetylase inhibitor, AR-42, inhibits gp130\/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells","volume":"129","author":"Zhang","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5530","DOI":"10.1021\/jm0503749","article-title":"Structure-based optimization of phenylbutyrate-derived histone deacetylase inhibitors","volume":"48","author":"Lu","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1021\/jm0303655","article-title":"Zn2+-chelating motif-tethered short-chain fatty acids as a novel class of histone deacetylase inhibitors","volume":"47","author":"Lu","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Yudaev, P., Aleksandrova, Y., and Neganova, M. (2025). Recent Insights into the Creation of Histone Deacetylase Inhibitors for the Treatment of Human Diseases. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178629"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"31134","DOI":"10.18632\/oncotarget.5290","article-title":"HDAC inhibitor AR-42 decreases CD44 expression and sensitizes myeloma cells to lenalidomide","volume":"6","author":"Canella","year":"2015","journal-title":"Oncotarget"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1002\/hep.21804","article-title":"Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma","volume":"46","author":"Lu","year":"2007","journal-title":"Hepatology"},{"key":"ref_45","first-page":"422","article-title":"Inhibition of cell growth and induction of apoptosis in bladder cancer cell lines by a novel histone deacetylase inhibitor derived from phenylbutyrate","volume":"65","author":"Mortazavi","year":"2005","journal-title":"AACR J. Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.bbrc.2015.05.078","article-title":"The novel HDAC inhibitor AR-42-induced anti-colon cancer cell activity is associated with ceramide production","volume":"463","author":"Xu","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1158\/0008-5472.CAN-12-1888","article-title":"Histone deacetylase inhibitor AR-42 differentially affects cell-cycle transit in meningeal and meningioma cells, potently inhibiting NF2-deficient meningioma growth","volume":"73","author":"Burns","year":"2013","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1208\/s12248-016-9876-3","article-title":"Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents","volume":"18","author":"Cheng","year":"2016","journal-title":"AAPS J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1080\/10428194.2017.1298751","article-title":"A phase 1 trial of the HDAC inhibitor AR-42 in patients with multiple myeloma and T- and B-cell lymphomas","volume":"58","author":"Sborov","year":"2017","journal-title":"Leuk. Lymphoma"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"126","DOI":"10.18632\/oncoscience.417","article-title":"A new concept in NF2 pharmacotherapy: Targeting fatty acid synthesis","volume":"5","author":"Stepanova","year":"2018","journal-title":"Oncoscience"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2867\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:53:33Z","timestamp":1774259613000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2867"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,22]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062867"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062867","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,22]]}}}