Targeting QRICH1 suppresses epithelial-mesenchymal transition and tumor growth in liver cancer through the Connexin43/USP1 mediated Snail1 stabilization.

Although glutamine-rich protein 1 (QRICH1) has been implicated in endoplasmic reticulum stress-associated epithelial-mesenchymal transition (EMT), its mechanistic role in liver cancer progression remains unclear. QRICH1 expression was analyzed in public datasets and clinical liver cancer specimens. Gain- and loss-of-function approaches were performed to assess proliferation, migration, invasion, and EMT signaling in vitro, and tumorigenicity was evaluated using a xenograft mouse model. QRICH1 was significantly overexpressed in liver cancer tissues with poor clinical outcomes. QRICH1 silencing markedly suppressed cell proliferation, migration, invasion, and EMT, accompanied by decreased Snail1 and ZEB1 expression and restoration of Connexin43 (GJB1). Co-immunoprecipitation and immunofluorescence analyses demonstrated that QRICH1 physically interacted and colocalized with Snail1 and USP1. Molecular docking further supported stable binding interfaces among these proteins. Ubiquitination and cycloheximide chase assays revealed that QRICH1 enhanced Snail1 protein stability through USP1-mediated deubiquitination. Functionally, QRICH1 suppressed gap junction intercellular communication, consistent with reduced Connexin43 expression, but not Connexin26 and Connexin32. In vivo, QRICH1 knockdown significantly inhibited tumor growth and reduced the expression of USP1, Snail1, PCNA, VEGF, and N-cadherin, while increasing E-cadherin and Connexin43. Collectively, these findings identify QRICH1 as a key oncogenic regulator that promotes liver cancer progression by stabilizing Snail1 via USP1-dependent deubiquitination and disrupting Connexin43-mediated gap junction signaling.