Abstract

Colorectal cancer (CRC) ranks as the third most common malignancy worldwide, with metastasis representing the primary cause of mortality. Aberrant activation of the Wnt/β-catenin pathway drives epithelial‒mesenchymal transition (EMT) and CRC metastasis, making β-catenin a key therapeutic target. Josephin domain containing 2 (JOSD2), a deubiquitinase with protumorigenic roles in multiple cancers, has an undefined function in CRC metastasis. Herein, by screening a protein homeostasis-related inhibitor library, we identified HY041004, a reported JOSD2 inhibitor, which potently suppresses β-catenin transcriptional activity. Mechanistically, JOSD2 modulates β-catenin protein abundance and functional activity via the RAS-ERK signaling cascade rather than through direct deubiquitination of β-catenin. Functional assays further demonstrated that JOSD2 inhibition via RNA interference or pharmacological inhibition significantly attenuated CRC metastasis both in vitro and in vivo. Collectively, our findings identify JOSD2 as a critical oncogenic factor that promotes β-catenin activity and validate JOSD2 as an underlying therapeutic target for metastatic CRC (mCRC).