PSMD1 inhibition suppresses tumor progression and enhances antitumor immunity by modulating the RTKN/β-catenin/PD-L1 axis in hepatocellular carcinoma.

Immunotherapy has emerged as a promising approach in the management of cancer. However, the suboptimal efficacy of immunotherapy monotherapy underscores the need to develop more effective combination strategies. In this study, we focused on PSMD1 to investigate its role and the molecular pathways by which it regulates the response to immunotherapy in hepatocellular carcinoma (HCC). In HCC, elevated PSMD1 levels are linked to associated with poor prognosis. PSMD1 was predominantly expressed in malignant epithelial cells. Tissue microarray results showed that PSMD1 was highly expressed in tumor tissues. Silencing PSMD1 suppressed HCC cell proliferation and promoted apoptosis in both in vitro and in vivo models. Additionally, PSMD1 suppression decreased PD-L1 expression, thereby enhancing the therapeutic efficacy of anti-PD-1 therapy. Mechanistically, publicly available single-cell RNA sequencing (scRNA-seq) datasets indicated that PSMD1 positively regulates β-catenin signaling. Silencing of PSMD1 decreased the expression of β-catenin pathway-associated proteins. Further analysis via mass spectrometry revealed that PSMD1 interacts with Rhotekin (RTKN) and suppresses its ubiquitination. Subsequent experiments revealed that RTKN enhances β-catenin expression through AKT phosphorylation, thereby increasing PD-L1 transcription. In summary, our findings demonstrate that PSMD1 regulates RTKN protein expression, whereas RTKN facilitates β-catenin expression via AKT phosphorylation. This mechanism contributes to HCC progression and the effectiveness of immunotherapy. The PSMD1/RTKN/β-catenin axis could serve as a promising therapeutic target for HCC.