Loss of tuberous sclerosis complex 2 confers inflammation via dysregulation of nuclear factor kappa-light-chain-enhancer of activated B cells

McPhail, Darius K., Alzahrani, Mohammad A.M., Martin, Katie R., Calver, Brian L., Harwood, Adrian J. ORCID: https://orcid.org/0000-0003-3124-5169, MacKeigan, Jeffrey P., Davies, David M. and Tee, Andrew R. ORCID: https://orcid.org/0000-0002-5577-4631 2025. Loss of tuberous sclerosis complex 2 confers inflammation via dysregulation of nuclear factor kappa-light-chain-enhancer of activated B cells. Journal of Inflammation 22 (1) , 38. 10.1186/s12950-025-00464-8

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Abstract

Background: Aberrant activation of mTORC1 is clearly defined in TSC and causes uncontrolled cell growth. 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-κB. This study aimed to characterise NF-κB in the context of TSC. Results: Enrichment of NF-κB-regulated genes was observed in TSC patient tumours, SEN/SEGAs, cortical tubers, and a TSC tumour-derived cell line (621 − 101). Highlighting an inflammatory component of TSC, TSC cell models exhibit elevated NF-κB and STAT3 activation. Herein, we report a dysregulated inflammatory phenotype in TSC2-deficient cells in which NF-κB promotes autocrine signalling involving IL-6. Notably, mTORC1 inhibition does not block this inflammatory signal to promote STAT3, while NF-κB inhibition is much more effective. Combined mTORC1 and NF-κB inhibition potently prevented the anchorage-independent growth of TSC2-deficient cells, whereas mTORC1 inhibition alone was insufficient to prevent colony regrowth after cessation of treatment. Conclusion: This study reveals autocrine signalling crosstalk between NF-κB and STAT3 in TSC cell models. Furthermore, the data presented indicate that NF-κB pathway inhibitors could be a viable adjunct therapy to the currently available mTORC1 inhibitors for treating TSC.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	BioMed Central
ISSN:	1476-9255
Date of First Compliant Deposit:	1 October 2025
Date of Acceptance:	19 August 2025
Last Modified:	01 Oct 2025 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/181429

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