Jul 2026· Pathology, Research and Practice· Vol 286, pp.
156633
· 0 citations· 37 references
Medicine
Abstract
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.
LINC01607 contributes to HCC progression and ferroptosis-associated therapy resistance, at least in part through the p62–Keap1–Nrf2 pathway, supporting further investigation of LINC01607 as a potential therapeutic target.
Yuxin Zhang, Weiqi Xu, Fangling Cheng et al.· Cancer Drug Resistance· 0 citations
BACKGROUND
Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality worldwide, with limited treatment options due to inherent chemotherapy resistance. Ferroptosis, an iron-dependent form of regulated cell death, has recently emerged as a promising strategy to overcome this resistance. Inducing ferroptosis may sensitize LUAD cells to chemotherapy, but its molecular regulators and therapeutic potential remain largely unexplored. This study aims to investigate the role of Distal-less homeobox 6 (DLX6) in regulating ferroptosis and its contribution to LUAD progression.
METHODS
To elucidate the function of DLX6 in LUAD, we employed a multi-omics approach, integrating TCGA data analysis, in vitro cell culture models, and in vivo xenograft experiments. Transcriptome sequencing, chromatin immunoprecipitation (ChIP) assays, and dual-luciferase reporter assays were utilized to uncover the underlying molecular mechanisms.
RESULTS
We found that DLX6 is significantly upregulated in LUAD and associated with poor patient prognosis. Functional studies showed that silencing DLX6 suppressed cell proliferation, triggered ferroptosis, and sensitized LUAD cells to chemotherapy. Mechanistically, DLX6 acted as a transcriptional activator of Glutathione Peroxidase 4 (GPX4), a central regulator of ferroptosis, by directly binding to its promoter region. Inhibition of DLX6 triggered ferroptosis in LUAD cells, enhancing treatment sensitivity to cisplatin.
CONCLUSIONS
Our findings highlight DLX6 as a key regulator of ferroptosis and cisplatin sensitivity in LUAD. By promoting GPX4 expression and inhibiting ferroptosis, DLX6 plays a crucial role in LUAD progression. This study provides valuable insights into the molecular mechanisms driving LUAD and offers a potential therapeutic target for sensitizing cisplatin treatment and improving chemotherapy resistance.
Zedong Sun, Minmin Zhou, Can Wang et al.· Cellular Oncology· 0 citations
Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, remains a significant therapeutic challenge due to its high mortality rates, driven by both inherent and acquired resistance to standard therapies. Emerging evidence highlights the role of epitranscriptomic regulation, particularly RNA modifications such as 5-methylcytosine (m5C), in the pathogenesis of cancer. This study identifies TRDMT1 (DNMT2), an m5C methyltransferase, as a tumor suppressor in LUAD. It was found that TRDMT1 expression is significantly lower in LUAD tissues, and this reduction is associated with poor prognosis in patients. Functional assays indicated that TRDMT1 inhibits the proliferation, migration, and invasion of LUAD cells in vitro. Mechanistically, transcriptomic profiling and subsequent investigation revealed that TRDMT1 enhances the stability of transferrin receptor (TFRC) mRNA in an m5C-dependent manner. This post-transcriptional regulation leads to TFRC upregulation, which subsequently disrupts intracellular iron homeostasis, culminating in increased susceptibility to ferroptosis-an iron-dependent form of regulated cell death. Rescue experiments confirmed that the tumor-suppressive and pro-ferroptotic effects of TRDMT1 are mediated through TFRC. This study unveils a novel TRDMT1-TFRC regulatory axis that suppresses LUAD progression through the modulation of ferroptosis, highlighting this pathway as a promising therapeutic target for future interventions.
Ying Zhu, Zuli Jiang, Youming Chen et al.· Journal of Biological Chemis...· 0 citations
BACKGROUND
Tumor-associated macrophages (TAMs), as core components of the triple-negative breast cancer (TNBC) tumor microenvironment (TME), can promote tumor progression. Ferroptosis has been shown to be involved in TNBC progression, but its regulatory mechanisms in TNBC TAMs remain incompletely understood.
METHODS
Clinical samples of TNBC were collected, and in vitro co-culture systems and BC xenograft models were established. By combining the results of the TCGA-BRCA and METABRIC transcriptomic cohort analyses, the expression characteristics and immune associations of ACOD1 were examined. Functional exploration was conducted through CCK-8, EdU, and colony formation assays and the detection of ferroptosis-related indicators. Molecular mechanisms were investigated using co-immunoprecipitation (Co-IP), CETSA, DARTS, SPR, and molecular docking.
RESULTS
ACOD1 expression was upregulated in immune-infiltrated subtypes, such as Basal-like/TNBC and HER2-enriched subtypes and significantly positively correlated with the infiltration of myeloid immune cells, including macrophages. Further results revealed that ACOD1 is highly expressed in TNBC TAMs and is driven by TME signals, independent of the classical M2 polarization pathway. The knockdown of ACOD1 in TAMs inhibited MDA-MB-231 cell proliferation and in vivo tumor growth and reduced ferroptosis resistance in TAMs. Mechanistically, ACOD1 knockdown did not affect KEAP1 expression but did reduce the expression of NRF2 and its downstream target genes HO-1 and NQO1, decreased NRF2 nuclear translocation, and increased KEAP1-NRF2 binding. Knockdown of KEAP1 or overexpression of NRF2 enhanced ferroptosis resistance. Additionally, ACOD1 knockdown decreased itaconate (ITA) levels in TAMs. The ITA derivative 4-OI was directly bound to KEAP1, weakened the KEAP1-NRF2 interaction, inhibited NRF2 ubiquitination, and stabilized NRF2 expression.
CONCLUSION
ACOD1, through its enzymatic product ITA, promotes ITA binding to KEAP1, which inhibits the KEAP1-NRF2 interaction and thus activates NRF2-mediated antioxidant and ferroptosis resistance responses in TAMs, promoting TNBC progression.
Jie Yang, Xiyin Li, Xin Qu et al.· Pathology, Research and Prac...· 0 citations
BACKGROUND
Ferroptosis resistance is a major challenge in cancer therapy, contributing to poor prognosis and unsatisfactory treatment outcomes. Thus, identifying key regulators of ferroptosis is essential for developing strategies to overcome this limitation. Mixed lineage kinase domain-like protein (MLKL) is well established as the executioner of necroptosis, but emerging evidence suggests broader functions beyond necroptosis. A previous study demonstrated that MLKL regulates ferroptosis in an acute kidney injury model. However, its role in ferroptosis regulation in cancer remains largely unexplored.
RESULTS
Bioinformatics analyses revealed that MLKL expression positively correlates with glutathione metabolism-related genes in colorectal cancer (CRC) patients and with reduced sensitivity to GPX4 inhibitors across pan-cancer cell lines. Functional studies demonstrated that MLKL depletion sensitizes not only CRC cells but also multiple cancer cell types to ferroptosis induced by GPX4 inhibitors. Mechanistically, MLKL-deficient CRC cells exhibited reduced intracellular glutathione levels and dysregulation of the NRF2/KEAP1/SLC7A11 antioxidant axis. However, KEAP1 knockdown in MLKL-depleted cells partially reduced ferroptosis sensitivity, indicating that additional mechanisms are involved. Proteomic analysis identified CHMP5, a component of the ESCRT-III membrane repair machinery, as a key downstream effector associated with MLKL. MLKL depletion suppressed CHMP5 expression and impaired its translocation to the plasma membrane during ferroptosis induction. Consistent with defective membrane repair, MLKL-knockdown CRC cells exhibited increased HMGB1 release following GPX4 inhibitor treatment, indicating enhanced membrane damage. Notably, CHMP5 overexpression reduced ferroptosis in MLKL-knockdown cells, highlighting that MLKL regulates ferroptosis susceptibility in part through CHMP5-dependent ESCRT-III signaling.
CONCLUSIONS
This study reveals a previously unrecognized role for MLKL in ferroptosis regulation through coordinating NRF2/KEAP1/SLC7A11-mediated glutathione metabolism and ESCRT-III-dependent membrane repair. These findings identify MLKL as a potential regulator of ferroptosis resistance and warrant further studies to evaluate the therapeutic relevance of MLKL-targeting strategies in colorectal cancer.
Sasiprapa Sonkaew, Nattaya Duangthim, C. Butkinaree et al.· Biology Direct· 0 citations
Glioblastoma (GBM) is one of the most aggressive and treatment-resistant tumors of the central nervous system, demanding innovative therapeutic strategies. Ferroptosis, an iron-driven lipid peroxidation-dependent cell death, has emerged as a potential means to overcome resistance, with glutathione peroxidase 4 (GPX4) as its key suppressor. MLN4924 (pevonedistat), a first-in-class inhibitor of neddylation currently in clinical trials, has shown strong antitumor activity across multiple malignancies. However, its role in ferroptosis regulation and the underlying molecular mechanisms remain poorly defined. Here, we show that MLN4924 induces ferroptosis, with GPX4 emerging as a central regulatory node. GPX4 expression is elevated in gliomas compared to normal brains, and its higher levels correlate with increased grades and worse patient prognosis. MLN4924 downregulates GPX4 mRNA by suppressing STAT3 signaling, whereas RSL3 directly inhibits GPX4 enzymatic activity. The combination of MLN4924 and RSL3 synergistically potentiates ferroptosis and, in vivo, suppresses subcutaneous tumor growth with a considerable biosafety. Collectively, these findings identify GPX4 as the principal mediator of MLN4924-induced ferroptosis and establish that dual targeting of GPX4 transcription and activity represents a promising therapeutic strategy for GBM.
Zhou Jing, Fangyuan Wang, Hao Li et al.· Carcinogenesis· 0 citations
