Aug 2026· Cancers· Vol 18· 0 citations· 50 references
Medicine
TL;DR
A key role is found for NF-κB/Lipocalin 2 (LCN2)-signaling-pathway-induced ferroptosis in modulating cisplatin sensitivity of V600E-overexpressing CRC cells to cisplatin within a KRAS-mutant cellular background, implying LCN2 as a potential therapeutic target.
Abstract
Simple Summary Colorectal cancer (CRC) driven by the BRAFV600E (V600E) mutation represents one of the most clinically challenging subtypes of the disease, characterized by rapid progression and a striking resistance to conventional chemotherapy. Despite its poor prognosis, the molecular mechanisms have remained unclarified. In this study, we found a key role for NF-κB/Lipocalin 2 (LCN2)-signaling-pathway-induced ferroptosis in modulating cisplatin sensitivity of V600E-overexpressing CRC cells to cisplatin within a KRAS-mutant cellular background. The results show that V600E overexpression cells exhibit suppressed NF-κB/LCN2 activation and insensitivity to cisplatin treatment. The NF-κB/LCN2 signaling could induce ferroptosis through increasing the accumulation of iron, leading to activation of the Fenton reaction and increasing ROS levels. Restoring LCN2 expression in V600E overexpression cells could partially attenuate the inhibition of ferroptosis and chemoresistance of cisplatin. Interestingly, we further found an unexpected interplay between ferroptosis and apoptosis, which is also regulated by LCN2. Taken together, these findings imply LCN2 as a potential therapeutic target. Aiming the crosstalk between ferroptosis and apoptosis may offer a potential strategy to overcome chemotherapy resistance of this high-risk CRC subtype.
Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options, highlighting the urgent need to identify novel therapeutic targets. The present study investigates the role of the RNA methyltransferase METTL3 in promoting TNBC progression by modulating a ferroptosis-related phenotype, an iron-dependent form of regulated cell death. Using TNBC cell lines (BT549 and MDA-MB-231), we demonstrated that METTL3 overexpression significantly enhanced cell proliferation, while its knockdown suppressed growth. Mechanistically, METTL3 was associated with decreased lipid peroxidation, reactive oxygen species (ROS), intracellular Fe2 + levels, and the pro-ferroptotic protein ACSL4, alongside increased glutathione and the key ferroptosis inhibitor GPX4. Bioinformatic analysis, MeRIP-PCR, and actinomycin D chase assays indicated that METTL3 was associated with increased N6-methyladenosine (m6A) enrichment, expression, and persistence of ELF1 mRNA. Dual-luciferase reporter assay further suggested that ELF1 may be involved in GPX4 transcriptional regulation. Crucially, the pro-proliferative and ferroptosis-associated effects of METTL3 overexpression were partially attenuated upon ELF1 knockdown or treatment with the ferroptosis inducer erastin. In conclusion, our findings suggest a novel METTL3/ELF1/GPX4 axis through which METTL3 promotes TNBC growth by regulating oxidative stress and ferroptosis-related markers, providing a basis for further investigation of this pathway in the context of TNBC biology and therapeutic development.
Jin-Chen Wang, Wei Wang, Jun-Jie Hu et al.· Asia-Pacific Journal of Clin...· 0 citations
Background PD‐1 blockade has yet to achieve broad clinical success in colorectal cancer (CRC), with microsatellite‐stable tumors proving especially resistant. At the same time, ferroptosis has emerged as a mechanistic link between redox control in tumor cells and the antitumor immune response. GPR39 is overexpressed in CRC, but its functional role in ferroptosis and immunotherapy resistance is currently unclear. Methods GPR39 expression was analyzed in human and mouse CRC cell lines. GPR39 knockdown, with or without the ferroptosis inhibitor liproxstatin‐1, was performed to determine whether GPR39 regulates CRC cell proliferation and migration through ferroptosis. Ferroptosis was evaluated by measuring lipid peroxidation, glutathione (GSH) levels, ferrous iron (Fe2+) accumulation, and reactive oxygen species (ROS). Mechanistic involvement of the nuclear factor erythroid 2–related factor 2 (Nrf2)/solute carrier family 7 member 11 (SLC7A11) signaling axis was examined using Nrf2 overexpression. Subcutaneous implantation of MC38 cells with stable GPR39 knockdown was performed to evaluate whether GPR39 regulates tumor sensitivity to anti‐PD‐1 treatment in vivo in a ferroptosis‐dependent manner. Results GPR39 was markedly upregulated in CRC cell lines. GPR39 knockdown induced ferroptosis, characterized by increased lipid peroxidation, Fe2+ accumulation, and oxidative stress and accompanied by suppression of the Nrf2/SLC7A11 pathway. Nrf2 overexpression reversed these changes. Functionally, silencing GPR39 inhibited the proliferative and migratory capacities of CRC cells, effects that were largely rescued by liproxstatin‐1. In vivo, GPR39 knockdown significantly potentiated the antitumor activity of PD‐1 blockade, as evidenced by suppressed tumor progression accompanied by enhanced infiltration of CD8+ T cells, whereas ferroptosis inhibition abrogated these effects. Conclusion GPR39 suppresses ferroptosis in CRC via the Nrf2/SLC7A11 axis, thereby limiting PD‐1 immunotherapy efficacy.
Cong Zhou, Xiao-Ling Fang, Jia-Ying Lin et al.· Canadian Journal of Gastroen...· 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
Glioma represents one of the most aggressive tumors in the central nervous system, with clinical management facing significant challenges including high recurrence rates and therapeutic resistance. Ferroptosis, an iron-dependent form of cell death, holds potential for glioma treatment, yet tumor cells frequently develop evasion mechanisms. This study elucidates the molecular mechanisms by which hypoxic microenvironment confers ferroptosis resistance in glioma cells, focusing on the pivotal role of the HIF-1α/SREBP1 signaling axis and its downstream effectors FASN and SCD1. Our experimental results demonstrate that hypoxic conditions significantly upregulate HIF-1α expression and confer resistance to RSL3-induced ferroptosis. Mechanistic studies reveal that HIF-1α promotes SREBP1 activation, which subsequently upregulates FASN and SCD1 expression to suppress lipid peroxidation.Furthermore, the HIF-1α-specific inhibitor PX-478 effectively reverses hypoxia-induced ferroptosis resistance and significantly enhances tumor cell sensitivity to ferroptosis inducers. In vivo experiments confirm the potent antitumor effects of PX-478 combined with RSL3. This study systematically elucidates the role of the HIF-1α-SREBP1-FASN/SCD1 signaling axis in ferroptosis regulation in glioma, providing important theoretical foundations and experimental support for developing HIF-1α-targeted ferroptosis therapies.
Zhong-Jun Shen, Yao Zhao, Mingbo Jia et al.· Journal of Lipid Research· 0 citations
Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC) with higher incidence rates in India. Ionizing radiation (IR) is a key component of TNBC treatment regimens. However, overall suboptimal response during the course of multiple repeat radiotherapy with eventual attainment of radioresistance remains a major challenge for this oncologic treatment modality. To overcome this limitation, it is important to understand molecular signatures that drive cells to transform into non-responsive populations against radiation therapy. Here, we demonstrate a constitutively high basal level of autophagy in TNBC cells, which might contribute to their relatively lower sensitivity to radiation-induced cell death. We also observed an elevated level of p62 in TNBC cells, which is regulated independently of autophagic flux. Concurrent upregulation of p62 and basal level of autophagy were found to be the driving forces in acquiring radioresistance in breast cancer cells. Ectopic expression of p62 enabled breast cancer cells to proliferate rapidly with enhanced migration potential. Reciprocally, posttranscriptional or pharmacological inhibition of p62 prevented the proliferation and migration potential of TNBC cells. Our high-throughput next-generation sequencing (NGS) data revealed VCAM-1 as a key mediator in p62-driven cell proliferation and acquired radioresistance. Likewise, impairment of autophagic flux, either by pharmacological inhibitors (CQ and bafA1) or by genetic deletion of ATG5, led to reversal of radioresistance. Collectively, our data highlight that an elevated basal level of autophagy with co-induction of p62 de novo protein synthesis confers radioresistance in TNBC.
Nisha Yadav, Anusha Banerjee, Tanzeela et al.· Cell Death Discovery· 0 citations
Osteosarcoma continues to exhibit poor survival outcomes due to chemoresistance and metastasis, with metabolic reprogramming and ferroptosis resistance being key features of tumor heterogeneity, yet their upstream regulators remain poorly defined. NFS1, a cysteine desulfurase essential for iron–sulfur cluster biogenesis, protects multiple cancers from ferroptosis, but its role in osteosarcoma is unknown. In this study, we performed a transcriptomic meta-analysis and found that NFS1 expression was significantly upregulated in osteosarcoma tissues, with further elevation in metastatic lesions, and high NFS1 expression correlated with poor overall survival. Genome‑wide CRISPR screening data revealed a marked NFS1 dependency in osteosarcoma cell lines. Functionally, NFS1 promoted cell proliferation, migration, and invasion, whereas its knockdown suppressed these phenotypes. Using single‑cell RNA sequencing data from 27 osteosarcoma specimens, we applied a multi‑algorithm glycolytic scoring framework and observed NFS1 enrichment in highly glycolytic malignant cells, along with an association with PI3K/AKT/mTOR pathway activation. Mechanistically, NFS1 selectively enhanced PI3K, AKT, and mTOR phosphorylation without altering total protein levels, and upregulated GPX4, a central ferroptosis suppressor, leading to elevated ferroptosis resistance scores in NFS1‑high malignant cells. Collectively, these findings identify a previously unrecognized NFS1–PI3K/AKT/mTOR–GPX4 regulatory axis in osteosarcoma, linking metabolic reprogramming to ferroptosis resistance, and suggest that NFS1 functions as an oncogenic driver, as well as a promising prognostic biomarker and therapeutic target in osteosarcoma.
Yu-Nan Man, Jing-Tang Li, Tao Zhang et al.· Functional & Integrative Gen...· 0 citations
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