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

Sep 22, 2026

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Immunotherapy for hepatocellular carcinoma shows limited effectiveness as monotherapy, motivating development of stronger combinational strategies. PSMD1 is identified as a key gene in this context, with higher PSMD1 levels associated with poor prognosis and enriched expression in malignant epithelial cells. Functional studies show that PSMD1 silencing suppresses HCC proliferation and promotes apoptosis while reducing PD-L1 and improving anti–PD-1 efficacy. Mechanistically, PSMD1 modulates the RTKN/β-catenin pathway, involving interaction and altered ubiquitination of RTKN and AKT-driven β-catenin activity that increases PD-L1 transcription, promoting tumor progression and shaping immunotherapy response.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages12

Reading Time30 min

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Introduction

Clinical challenge in advanced HCC immunotherapy

Machine learning identification of PSMD1 and proteasome biology

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN PSMD1 inhibition suppresses tumor progression and enhances antitumor immunity by modulating the RTKN/β-catenin/PD-L1 axis in hepatocellular carcinoma Xiangjun Qian 1,4, Kai Zhang1,4, Chao Ma1,4, Yang Ji2, Xianzhou Zhang1, Li Wang1, Tao He1, Haibo Yu3 ✉, Hao Zhuang 1 ✉ and Xiaopei Hao 1,2 ✉ © The Author(s) 2025 | | | | | --- | --- | --- | | | 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. | | | | | | | | | | | | Cell Death and Disease (2026)17:36; [https://doi.org/10.1038/s41419-025-08241-4](https://doi.org/10.1038/s41419-025-08241-4) | | | | | | INTRODUCTION Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the sixth most commonly diagnosed malignancy worldwide and the third leading cause of cancerrelated mortality globally [1] . The asymptomatic presentation of early-stage HCC often leads to delayed diagnosis, rendering many patients ineligible for curative surgical intervention. At present, multikinase inhibitors and immune checkpoint inhibitors (ICIs) constitute the cornerstone of therapeutic strategies for advanced HCC [2] . Among these agents, anti-PD-1 and anti-PD-L1 monoclonal antibodies have transformed the therapeutic landscape of solid tumors, including HCC [3] . Although a substantial number of patients have beneﬁted from immunotherapy, including those with advanced HCC who have subsequently become eligible for surgical resection, the efﬁcacy of immune checkpoint blockade (ICB) remains suboptimal, with response rates averaging only 20% [4] . Even when combined with targeted therapies, the overall response rate does not surpass 40%[5], highlighting the urgent need for more effective therapeutic strategies to address the unmet needs of a signiﬁcant patient population. Consequently, innovative strategies to increase the clinical efﬁcacy of ICB in HCCare urgently needed. With the advancement of detection technologies, the diversity of detection methods leads to increased variability in the generated data. To integrate these data and identify underexplored therapeutic targets, we utilized machine learning to train data models and identify genes associated with

FAQs

What is the main effect of inhibiting PSMD1 in hepatocellular carcinoma?

PSMD1 silencing suppresses HCC cell proliferation and promotes apoptosis in vitro and in vivo. It also reduces PD-L1 expression, strengthening the therapeutic efficacy of anti–PD-1 therapy.

How does PSMD1 influence the RTKN/β-catenin/PD-L1 axis?

PSMD1 positively regulates β-catenin signaling. Mechanistically, PSMD1 interacts with RTKN and suppresses its ubiquitination, and RTKN enhances β-catenin expression via AKT phosphorylation, which increases PD-L1 transcription.

Why is PD-L1 reduction important for immunotherapy response?

The study links PSMD1 suppression to decreased PD-L1 expression, which in turn enhances the efficacy of anti-PD-1 therapy. This connects the PSMD1–RTKN–β-catenin pathway to immunotherapy responsiveness in HCC.

Sep 22, 2026

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