Aug 2026· Molecular and Cellular Biochemistry· 0 citations· 49 references
Medicine
TL;DR
The therapeutic potency of Lomitapide was established to target Hippo pathway through disrupting ROCK activity in EMT dynamics, evident by upregulation of epithelial markers and downregulation of mesenchymal markers, through western blotting, qRT-PCR and immunofluorescence studies.
BACKGROUND
Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, characterized by aggressive progression and therapy resistance. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising therapeutic avenue. However, the role of Ribonucleotide Reductase M2 (RRM2) in ferroptosis regulation and its relevance to LUAD progression remain incompletely understood.
METHODS
We integrated bulk transcriptomic, proteomic, WGCNA, and single-cell datasets to evaluate the clinical and biological relevance of RRM2 in LUAD. Functional validation was performed using RRM2 knockdown, ferroptosis-inducer sensitivity assays, ferroptosis-related biochemical assays, NRF2/GPX4 pathway analysis, rescue experiments, and xenograft models.
RESULTS
RRM2 was significantly upregulated in LUAD tissues and was associated with poor overall survival. Single-cell analysis localized high RRM2 expression to a proliferative tumor cell subpopulation enriched in cell cycle- and immune-related pathways. Functionally, RRM2 knockdown suppressed LUAD cell proliferation and tumor growth and was accompanied by increased ROS, lipid ROS, Fe²⁺, and MDA levels and decreased GSH levels. RRM2 depletion also increased ferroptosis-inducer sensitivity, with enhanced erastin and RSL3 sensitivity in A549 cells and clear RSL3 sensitization in PC9 cells. In parallel, RRM2 silencing was associated with reduced NRF2 and GPX4 expression, decreased NRF2 nuclear-to-cytosolic signal intensity, and increased ACSL4 expression. NRF2 overexpression partially restored GPX4 immunofluorescence intensity in RRM2-knockdown cells. Moreover, NRF2 overexpression or Ferr-1 treatment partially reversed the growth-suppressive effects induced by RRM2 deficiency in vitro and in vivo.
CONCLUSION
RRM2 is associated with LUAD progression, ferroptosis-inducer sensitivity, and ferroptosis-related phenotypes, potentially through modulation of the NRF2/GPX4 axis. These findings support RRM2 as a candidate prognostic biomarker and a potential therapeutic target in LUAD, while the precise molecular relationship between RRM2 and the NRF2/GPX4 axis warrants further investigation.
Xiangyuan Li, Fenfen Gu, R. Xiao et al.· Pathology, Research and Prac...· 0 citations
It is demonstrated that activation of β-catenin is associated with a poor prognosis in melanoma and inhibiting the enzymatic activity of MICAL2 offers a promising and innovative strategy to improve outcomes in β-catenin-driven melanoma.
P. Sohier, J. Raymond, Zackie Aktary et al.· Cell Death and Differentiati...· 0 citations
It is demonstrated that Fraxetin exerts multi-faceted effects against colorectal cancer, including anti-cancer activity, synergy with chemotherapy, and restoration of 5-FU sensitivity in 5-FU-resistant CRC cells in vitro, through multi-target inhibition of the PI3K-Akt signaling pathway.
Min-Fang Guo, Liangdong Zhu, Jianjin Guo et al.· Biochemical and Biophysical...· 0 citations
BUB1 was significantly upregulated in UCEC tumors compared with normal endometrium, associated with advanced disease stage and reduced overall survival, confirming its role as an unfavorable prognostic biomarker and therapeutic target in UCEC.
Wajahat Ali, Md. Abdullah Al Mamun, Yi-Cheng He et al.· Future Journal of Pharmaceut...· 0 citations
These findings demonstrate that EZH2 inhibition promotes coordinated epigenetic remodeling and disrupts key oncogenic pathways in breast cancer cells, and suggest potential combinatorial strategies integrating EZH2 inhibition with other targeted or epigenetic therapies to enhance treatment efficacy, overcome resistance mechanisms, and improve clinical outcomes.
Thaís Amanda Damasceno Silva, E. V. Fernandes, Mayara Bocchi et al.· Clinical Breast Cancer· 0 citations
TAK1 is established as a key hub in cisplatin resistance and 5Z7 reverses resistance by targeting TAK1 to coordinately regulate NF-κB/p53 signaling, providing a foundation for potential clinical translation.
Wenyan Lu, Kunhao Tang, Zechen Wang et al.· Biochemical Pharmacology· 0 citations
