N6-methyladenosine (m6A), as the most abundant epitranscriptomic modification in eukaryotes, profoundly influences the metabolic fate of RNA. Meanwhile, ferroptosis, a regulated cell death modality driven by iron-dependent lipid peroxidation, has become a key component in tumor metabolic reprogramming. Increasing evidence suggests a deep interaction between m6A modification and ferroptosis, which plays a critical role in tumor occurrence and development, and treatment response. This review systematically elucidates the multidimensional regulatory mechanisms of m6A on ferroptosis regulatory factors, covering post-transcriptional modifications of the System Xc
−
/GSH/GPX4 antioxidant axis, iron metabolism-related proteins, and key enzymes of lipid peroxidation. It analyzes the dual role of the m6A-ferroptosis axis in tumor suppression and promotion, and then explores the function of this regulatory network in reshaping the tumor immune microenvironment and mediating treatment resistance. Finally, it looks forward to the translational potential of the m6A-ferroptosis interactive network as a novel biomarker and combination therapy target. Future research should integrate multi-omics and cutting-edge technologies to deeply analyze the spatiotemporal dynamic mechanism of this regulatory network in the occurrence and development of tumors, providing theoretical basis and new research directions for precise intervention in this interdisciplinary field.
Yu-Shuo Duan, Zi-Yi Xu, Jia-Hao Liang et al.· Frontiers in Cell and Develo...· 0 citations
INTRODUCTION
Sorafenib is a first-line therapy for hepatocellular carcinoma (HCC), but its clinical benefit is limited by significant interpatient variability in response. Identifying reliable candidate biomarkers associated with sorafenib treatment is critical for optimizing treatment strategies and improving patient outcomes.
METHODS
Samples in the GSE109211 dataset were divided into sorafenib-treated and control groups. Differentially expressed genes (DEGs) were screened using the limma package and filtered via LASSO and SVM-RFE algorithms to identify potential HCC biomarkers. CIBERSORT and ESTIMATE algorithms were used to evaluate immune infiltration and its correlation with candidate genes, followed by GSEA to explore enriched functional pathways. Regulatory networks were constructed using hTFtarget and ENCORI, and potential drugs were predicted by molecular docking. The expression and knockdown effects of RPS21 were validated in THLE-2 and HuH7 cells using qRTPCR, wound-healing, and Transwell assays.
RESULTS
Five sorafenib-treatment-associated candidate biomarkers were identified, including glutamic-oxaloacetic transaminase 1 (GOT1), out at first homolog (OAF), Xprolyl aminopeptidase 2 (XPNPEP2), cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2), and ribosomal protein S21 (RPS21). These genes were related to immune cell infiltration. In particular, the expression of OAF and CRISPLD2 was associated with immune scores. GSEA showed enrichment in pathways such as OXIDATIVE_ PHOSPHORYLATION and MYC_TARGETS. GOT1 stably bound to sorafenib, carbamazepine, and diclofenac. RPS21 was upregulated in HuH7 cells, and its knockdown impaired migration and invasion, validating its oncogenic role.
DISCUSSION
This study identified candidate biomarkers related to sorafenib treatment for HCC through computational analyses, experimentally validated the oncogenic function of RPS21, and predicted carbamazepine and diclofenac as potential combination therapies for precision treatment of HCC.
CONCLUSION
We identified HCC biomarkers associated with sorafenib treatment and the tumor immune microenvironment, predicted targeted drugs, and expanded the paradigm for precision therapy in HCC.
Mengru Zhan, Peng-Hui Li, Wan-Yi Wang et al.· Current Medicinal Chemistry· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
