ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicE3 Ubiquitin Ligases: Critical Roles in Cancer Progression and Therapeutic ImplicationsView all 3 articles
RARS1 Inhibits ENO1 Ubiquitination and Degradation to Protect Against Ferroptosis in Hepatocellular Carcinoma
Provisionally accepted
- 1Fuyang People’s Hospital of Anhui Medical University., Fuyang, China
- 2No 2 People's Hospital of Fuyang City, Fuyang, China
- 3Fuyang Normal University, Fuyang, China
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Background: Liver hepatocellular carcinoma (LIHC) is an aggressive malignancy with high recurrence and therapy resistance. Transplant rejection-related genes (ARRGs) have emerged as potential contributors to cancer progression. This study investigates the role of RARS1, a gene involved in protein synthesis, in LIHC progression and its therapeutic potential. Methods: AR-DEGs in LIHC were identified via differential expression and Cox regression analyses, followed by non-negative matrix factorization (NMF) to classify patients into molecular subtypes. Immune microenvironment, immune evasion, and stemness differences were assessed. Multi-omics datasets, including transcriptomic, single-cell, and spatial transcriptomics, were used to evaluate RARS1 expression. Bioinformatics and molecular biology techniques were employed to study RARS1's role in oncogenic pathways, immune modulation, and ferroptosis, including interaction with ENO1. Drug sensitivity analysis identified potential RARS1-targeting compounds. Results: Three LIHC subtypes with distinct immune landscapes and prognoses were identified. Cluster 1 exhibited high immune infiltration and poor response to immune checkpoint blockade. RARS1 was significantly overexpressed in LIHC and correlated with poor prognosis. Knockdown of RARS1 inhibited proliferation and migration of LIHC cells and influenced immune cell polarization. Mechanistically, RARS1 regulated the PI3K/AKT/GSK3β pathway and suppressed ferroptosis via ENO1. Drug analysis revealed AH.6809 as a potential inhibitor of RARS1, reducing its oncogenic effects in vitro. Conclusion: AR-DEG-based subtyping reveals distinct LIHC immune profiles. RARS1 promotes LIHC progression through oncogenic signaling and immune modulation, serving as a promising prognostic biomarker and therapeutic target. Targeting RARS1 with agents like AH.6809 may offer novel treatment strategies for LIHC.
Keywords: Arginyl-tRNA synthetase, ENO1, allograft rejection, Ubiquitination, ferroptosis
Received: 15 Aug 2025; Accepted: 18 Nov 2025.
Copyright: © 2025 Zang, Ma, Chen, Cui and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Jiangtao Yu, yhzy502@163.com
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