Abstract
Liver metastasis remains a major cause of mortality in patients with colorectal cancer (CRC). Here, we identify OTUD6B, a deubiquitinating enzyme of the OTU family, as a key driver of CRC liver metastasis. OTUD6B is upregulated in metastatic CRC tissues and is correlated with poor prognosis. Functionally, OTUD6B promotes CRC cell proliferation, migration, and invasion in vitro and enhances tumor growth and liver metastasis in vivo. Mechanistically, OTUD6B binds the KH domain of fragile X-related protein 1 (FXR1) via its N-terminal region and stabilizes FXR1 by removing K48-linked polyubiquitin chains in a catalytic activity-dependent manner. In turn, FXR1 binds and stabilizes MEK2 mRNA, leading to increased MEK2 expression and activation of ERK signaling. Notably, FXR1 also upregulates OTUD6B expression, establishing a feed-forward loop that amplifies the oncogenic OTUD6B–FXR1–MEK2/ERK axis. OTUD6B, FXR1, and MEK2 levels are positively correlated in clinical CRC liver metastasis samples. Crucially, the MEK2 inhibitor U0126 acts synergistically with OTUD6B silencing to suppress liver metastasis. Collectively, these findings delineate a previously unrecognized oncogenic cascade in which OTUD6B stabilizes FXR1 to activate MEK2/ERK signaling, thereby driving CRC liver metastasis. Dual targeting of OTUD6B and MEK2 may represent a promising therapeutic strategy for advanced CRC.
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Funding
This work was supported by the National Natural Science Foundation of China (No. 82460545 to XXC and No. 82360416 to HQY), and the Second Affiliated Hospital of Nanchang University Funding Program (No. 2022efyA02 to HQY).
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The study was approved by the Research Ethics Committee of the Second Affiliated Hospital of Nanchang University (Approval NO. 2025-97), and informed consent was obtained from all participating patients. Animal experiments were approved by the Nanchang University Animal Care Committee (Approval NO. NCULAE-20250509002) and conducted in strict accordance with the university’s guidelines for animal care and use.
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Lu, Y., Liu, J., Li, YN. et al. OTUD6B-mediated K48 deubiquitination of FXR1 forms a positive feedback loop activating MEK2/ERK signaling in colorectal cancer liver metastasis. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08812-z
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DOI: https://doi.org/10.1038/s41419-026-08812-z
