Open Access

ARTICLE

OTUD7B Activates the Caspase-8-RIPK1-NEMO Complex-Regulated NF-κB Pathway to Promote Triple-Negative Breast Cancer Metastasis

Fiona Tsui-Fen Cheng^1,2,#, Kung-Ju Chen^3,#, Jing-Quan Zheng^3,4,5, Hui-Wen Chiu^3,6,7, Hui-Yu Lin^2,3,8,*, Yuan-Feng Lin^3,9,*

1 Breast Cancer Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
2 School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan
3 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
4 Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
5 Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
6 Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
7 TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
8 Division of Breast Surgery and General Surgery, Department of Surgery, Cardinal Tien Hospital, Fu-Jen Catholic University, New Taipei City, Taiwan
9 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

* Corresponding Authors: Hui-Yu Lin. Email: ; Yuan-Feng Lin. Email:
# These authors contributed equally to this work

Oncology Research 2026, 34(10), 15 https://doi.org/10.32604/or.2026.081093

Received 23 February 2026; Accepted 17 July 2026; Issue published 14 September 2026

Abstract

Background: Metastatic dissemination of triple-negative breast cancer (TNBC) to distant organs, such as the lungs and brain, poses a significant threat to patient survival. Nevertheless, the molecular basis driving TNBC metastasis remains largely elusive. In the present study, we elucidated the role and underlying mechanism of OTU deubiquitinase 7B (OTUD7B) in promoting TNBC metastasis. Methods: The Cancer Genome Atlas (TCGA)/K-M Plotter databases were used for determining the prognostic significance of OTUD7B in TNBC patients. Cell migration and lung colony-forming assays were performed to evaluate the metastatic potential of TNBC cells. A cycloheximide-chase assay was employed to examine the effect of OTUD7B on Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) Essential Modulator (NEMO) protein degradation in TNBC cells. Flow-cytometric analyses were performed to examine OTUD7B effects on TNBC necroptosis. Results: OTUD7B is significantly (p < 0.001) upregulated in TNBC and correlates with poor distant metastasis-free survival (log-rank p < 0.001, n = 424). Its knockdown suppresses, whereas overexpression enhances, the metastatic potential of TNBC cells in vitro and in vivo, dependent on its deubiquitinating activity. Mechanistically, OTUD7B regulates the ubiquitination of Caspase-8 and NEMO, thereby modulating NF-κB signaling through the Caspase-8–RIPK1–NEMO axis. OTUD7B depletion increases Caspase-8 activity by approximately three-fold, promotes NEMO degradation, suppresses NF-κB activation, and induces necroptosis. Conversely, OTUD7B overexpression exerts opposite effects. Pharmacological inhibition of NEMO or NF-κB attenuates OTUD7B-driven cell migration by 40–90%. Conclusions: The deubiquitinating activity of OTUD7B promotes TNBC metastasis by stabilizing the Caspase-8–RIPK1–NEMO axis, thereby activating the NF-κB signaling pathway. These results further suggest that targeting OTUD7B activity may be a promising therapeutic strategy for metastatic TNBC.

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