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While mTORC1 inhibitors show efficacy in stabilising tumour growth in patients with TSC, they are not fully curative. Disease facets of TSC that are not restored with mTOR inhibitors might involve NF-\u03baB. This study aimed to characterise NF-\u03baB in the context of TSC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Enrichment of NF-\u03baB-regulated genes was observed in TSC patient tumours, SEN\/SEGAs, cortical tubers, and a TSC tumour-derived cell line (621\u2009\u2212\u2009101). Highlighting an inflammatory component of TSC, TSC cell models exhibit elevated NF-\u03baB and STAT3 activation. Herein, we report a dysregulated inflammatory phenotype in\n                      <jats:italic>TSC2<\/jats:italic>\n                      -deficient cells in which NF-\u03baB promotes autocrine signalling involving IL-6. Notably, mTORC1 inhibition does not block this inflammatory signal to promote STAT3, while NF-\u03baB inhibition is much more effective. Combined mTORC1 and NF-\u03baB inhibition potently prevented the anchorage-independent growth of\n                      <jats:italic>TSC2<\/jats:italic>\n                      -deficient cells, whereas mTORC1 inhibition alone was insufficient to prevent colony regrowth after cessation of treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study reveals autocrine signalling crosstalk between NF-\u03baB and STAT3 in TSC cell models. Furthermore, the data presented indicate that NF-\u03baB pathway inhibitors could be a viable adjunct therapy to the currently available mTORC1 inhibitors for treating TSC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12950-025-00464-8","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T08:28:15Z","timestamp":1758875295000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Loss of tuberous sclerosis complex 2 confers inflammation via dysregulation of nuclear factor kappa-light-chain-enhancer of activated B cells"],"prefix":"10.1186","volume":"22","author":[{"given":"Darius K.","family":"McPhail","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad A.M.","family":"Alzahrani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie R.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Calver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian J.","family":"Harwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey P.","family":"MacKeigan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew R.","family":"Tee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,26]]},"reference":[{"key":"464_CR1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/bs.adgen.2018.11.003","volume-title":"Advances in Genetics","author":"LJ McEneaney","year":"2019","unstructured":"McEneaney LJ, Tee AR. 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Samples from TSC patients or non-TSC organ donors were acquired from the NIH NeuroBioBank\u2019s Brain and Tissue Repository at the University of Maryland, Houston-McGovern Medical School at the University of Texas, Cincinnati Children\u2019s Hospital Medical Center, New York University School of Medicine, and Helen DeVos Children\u2019s Hospital. Written informed consent was obtained from all human participants providing samples, and the study was approved by the Van Andel Research Institute (VARI) Institutional Review Board (IRB).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"38"}}