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Oncol."],"abstract":"<jats:p>\n                    Birt-Hogg-Dub\u00e9 (BHD) syndrome, caused by mutations in the tumor suppressor gene\n                    <jats:italic>FLCN<\/jats:italic>\n                    , has traditionally been classified as a classic \u201cmTORopathy\u201d characterized by global mTORC1 activation. Recent structural and multi-omic studies have fundamentally challenged this view, revealing that FLCN functions as a GAP for RagC\/D to govern substrate-selective mTORC1 regulation. Synthesizing emerging evidence, we describe an integrated pathogenic framework: biallelic\n                    <jats:italic>FLCN<\/jats:italic>\n                    inactivation drives renal tumorigenesis via constitutive MiT\/TFE nuclear accumulation and metabolic reprogramming, whereas haploinsufficiency suffices to disrupt structural integrity in the lung and skin. By reconciling the \u201cmTORC1 paradox\u201d through the lens of gene dosage and temporal signaling dynamics, we highlight novel therapeutic vulnerabilities targeting MiT\/TFE factors and kinase rewiring, providing a rationale for organ-specific precision medicine in BHD.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1848740","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:42:02Z","timestamp":1784695322000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Substrate-selective mTORC1 regulation and gene dosage\u2013dependent tissue divergence in Birt\u2013Hogg\u2013Dub\u00e9 syndrome"],"prefix":"10.3389","volume":"16","author":[{"given":"Zhi-Lie","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Urology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Enze Hospital of Hangzhou Medical College, Taizhou Enze Medical Center (Group)","place":["Taizhou, China"]},{"name":"Department of Urology, The 903rd Hospital of the Joint Logistics Support Force, Affiliated Xihu Hospital Hangzhou Medical College","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Cheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Ultrasound Medicine, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Enze Hospital of Hangzhou Medical College, Taizhou Enze Medical Center (Group)","place":["Taizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Lin","sequence":"additional","affiliation":[{"name":"Luqiao Hospital, Taizhou Enze Medical Center (Group)","place":["Taizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-Huang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, The Affiliated Jinling Hospital of Nanjing University Medical School","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu-Tao","family":"Hong","sequence":"additional","affiliation":[{"name":"The Fifth Hospital of Xiamen","place":["Xiamen, Fujian, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling-Ye","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine, School of Public Health, Wenzhou Medical University","place":["Wenzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Qi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Urology, The 906th Hospital of the Joint Logistics Support Force","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei-Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Enze Hospital of 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