ArticleJournal of advanced research2025
Tetrahydrocurcumin targets TRIP13 inhibiting the interaction of TRIP13/USP7/c-FLIP to mediate c-FLIP ubiquitination in triple-negative breast cancer.
Article in Journal of advanced research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- S100A9 modulates USP7-mediated stabilization of NCOA4 to promote ferroptosis in sepsis-associated acute lung injury.Redox biology · 2026Article
- Curcumin and Its Derivatives as Anticancer Agents in Head and Neck Cancer: Molecular Mechanisms and Preclinical Evidence.International journal of molecular sciences · 2026Review
- c-FLIP as a master regulator of immune homeostasis and disease mechanisms.Cell death & disease · 2026Review
- Emerging roles of USP7 in tumor immune evasion, metabolic reprogramming, and therapeutic resistance.Frontiers in immunology · 2026Review
- Stage-Specific Regulation of Ubiquitination Modifications and Prospects for Targeted Therapy in Triple-Negative Breast Cancer.Oncology research · 2026Review
- Multi-omics analysis and functional validation reveal the oncogenic role of TRIP13.Frontiers in immunology · 2026Article
- In Silico Integrated Systems Biology Analysis of Gut-Derived Metabolites from Philippine Medicinal Plants Against Atopic Dermatitis.International journal of molecular sciences · 2025Article
- Decoding TRIP13's Role in Gastric Cancer: Implications for Prognosis and Immune Response.Biomedicines · 2025Article
- TRIP13-induced NUSAP1 upregulation promotes CcRCC progression through EMT and PI3K/AKT/mTOR pathway.Journal of translational medicine · 2025Article
- Bardoxolone displays potent activity against triple negative breast cancer by inhibiting the TRIP13/STAT3 circuit.Acta pharmacologica Sinica · 2025Article
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13 authors.
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Abstract
introductionTriple-negative breast cancer (TNBC) has a high mortality rate and limited treatment options. Tetrahydrocurcumin (THC), a major metabolite of curcumin, has potential antitumor activities. However, the antitumor effects and mechanism of THC in TNBC remain elusive.
objectivesTo investigate the mechanism of THC in combating TNBC by targeting TRIP13 to disrupt the interaction of the TRIP13/USP7/c-FLIP complex and mediate c-FLIP ubiquitination both in vitro and in vivo.
methodsApoptosis was measured by TUNEL and flow cytometry. Click chemistry-based target fishing, CETSA, DARTS, and SPR were used to identify direct target of THC. Protein interactions was examined using co-immunoprecipitation. The role of USP7 in THC-mediated c-FLIP ubiquitination was evaluated by in vitro deubiquitination assay. Human breast cancer clinical samples were employed to assess the expression of c-FLIP, TRIP13, and USP7. The impact of THC on USP7/TRIP13/c-FLIP was analyzed using co-immunoprecipitation, confocal microscopy, molecular docking and dynamics simulations.
resultsTHC effectively inhibits TNBC cell proliferation and tumor growth in vitro and in vivo without significant toxicity. Mechanistically, THC induces extrinsic apoptosis in TNBC primarily by promoting degradation of c-FLIP, a key negative regulator in the apoptotic pathway. Furthermore, utilizing click chemistry-based target fishing, we identified TRIP13, a component of the highly conserved AAA ATPase family, as a direct target of THC in combating TNBC. Interestingly, contrary to previous drug-target studies, the knockdown of TRIP13 further amplified the antitumor effects of THC. After in-depth investigation, it was revealed that TRIP13 forms a trimeric complex with USP7 and c-FLIP in TNBC cells. THC specifically targets TRIP13 to disrupt the interaction of TRIP13/USP7/c-FLIP, leading to the ubiquitination of c-FLIP, ultimately inducing extrinsic apoptosis.
conclusionsThese findings offer new insights into the novel molecular mechanisms of anti-TNBC effects of THC and present a promising targeted therapeutic strategy for TNBC.
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