RSL3

Importantly, combining GTN with the ferroptosis inducer RSL3 synergistically enhances antitumor efficacy in vivo. Our study unveils a previously unrecognized KDM5B/ferroptosis axis through which GTN exerts its antitumor effects, positioning GTN as a promising lead compound for ferroptosis-targeted therapy in RCC.

In mouse models of melanoma and colorectal cancer, I3A administration significantly reduced the antitumor efficacy of the ferroptosis inducer RSL3, accompanied by reduced lipid peroxidation and preserved GPX4 levels. Furthermore, gut colonization with Lactobacillus reuteri increased I3A concentration and conferred ferroptosis resistance in vivo. Together, these findings identify a host-microbe metabolic axis in which microbial I3A suppresses cancer cell ferroptosis through AHR-JNK signaling, which may have critical implications for redox-based cancer therapies.

Firstly, the dual pathway specific enrichment strategy of O-GlcNAc modified peptides and N-glycosylated peptides was applied to ferroptosis study for the first time, which realized a systematic analysis of glycosylation patterns in the process of cell death. Secondly, high-resolution mass spectrometry combined with multi-platform data processing (MaxQuant/PEAKS) was used to deeply integrate transcriptomes and single-cell transcriptomes to construct a panoramic analysis framework with multi-omics mutual evidence. Thirdly, Scissor method was introduced to map TCGA ferroptosis pathway activity to single-cell data to achieve cross-scale analysis from population level to cell subsets. Fourth, combined with multi-dimensional bioinformatics tools, the characteristics of modification sites, subcellular localization, protein interaction network and functional pathway were annotated. Fifth, on the basis of multi-omics results, double-layer validation by qPCR and Western Blot at the transcriptional and protein levels significantly improved the credibility of the research conclusions. Its limitations are that the research mainly relies on high-throughput omics and computational analysis, and lacks systematic in vitro and in vivo functional verification and combination drug sensitivity experiments, as well as the support of real-world clinical cohorts.

Here, we reported a doxorubicin (DOX)-Fe complex and RSL3 co-loaded liposomes (DOX-Fe/RSL3@LIPs) for ferroptosis-enhanced chemotherapy on TNBC tumors. The tumor cell ferroptosis was observably enhanced via supplements of the ferrous ions and H2O2, and RSL3-derived GPX4 inhibition to severely destroy the oxidation balance in cells. In this paper, the DOX-Fe/RSL3@LIPs have exerted a synergistic anticancer effect on TNBC by combining ferroptosis and conventional chemotherapy, and made a meaningful exploration of new strategies for TNBC therapy.

Here we demonstrate that macrophages co-cultured with ferroptotic cancer cells from various types effectively mitigate cell death induced by GPX4 inhibitors (RSL3 and ML162), GPX4 silencing via shRNA, or the Xc- system inhibitor IKE...Furthermore, in placental villi explants, macrophages protect trophoblasts from ferroptotic death. These results underscore the intricate interplay between ferroptotic cells and their microenvironment and provide compelling evidence of a yet-unrecognized anti-ferroptotic activity of macrophages as a cell-extrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.

The HCC cells HepG2 and SNU449 were treated with five drugs, namely, dimethyl sulfoxide, AZ-628, SU-5402, TG-101209, and SPP-86, combined with donafenib to determine half-maximal inhibitory concentration values...Ferrous ion (Fe2+) and reactive oxygen species levels were measured after Erastin/RSL3 induction...In vivo experiments demonstrated a combined anti-tumor efficacy of AZ-628 and donafenib in HCC models (P < 0.0001). The findings of this study reveal a new combination therapy targeting the TK pathway for the treatment of HCC and provide a theoretical foundation for addressing donafenib resistance.

In line with this, HnRNPU deletion induced ferroptosis and increased sensitivity to RSL3 treatment and cysteine deprivation...Findings demonstrate that HnRNPU promotes proliferation and inhibits ferroptosis by regulating the mRNA stability of SLC7A11 and SLC3A2. Targeting HnRNPU is a potential therapeutic approach for COAD treatment.

Furthermore, the ferroptosis inducer RSL3 synergized with cisplatin to enhance ferroptosis and mitochondrial fragmentation, effectively sensitizing ACTG1-overexpressing cells both in vitro and in xenograft models. Our findings establish ACTG1 as a critical mediator of cisplatin resistance in NSCLC through regulation of mitochondrial integrity and ferroptosis. Targeting the ACTG1-MFN2 axis combined with ferroptosis induction represents a promising therapeutic strategy to overcome cisplatin resistance.

Importantly, ACSL6 knockdown increased GPX4 expression and colony growth, partially rescuing DHA-induced suppression, whereas ACSL6 overexpression enhanced DHA-mediated GPX4 reduction and colony inhibition, effects reversible by RSL3 or ferrostatin-1...In vivo, DHA supplementation potentiated oxaliplatin-suppressed tumor growth in tumors with upregulated ACSL6 expression, accompanied by GPX4 reduction. Together, these findings highlight ACSL6 as a critical determinant of DHA sensitivity in cancer, underscoring its potential as a predictive biomarker for chemotherapy-DHA combination strategies. By modulating key metabolic and signaling pathways, ACSL6 could influence cellular susceptibility to ferroptosis and may guide therapeutic approaches that enhance chemotherapy through DHA supplementation.

These findings suggest that inhibition of Complex II confers protection against ferroptosis by maintaining mitochondrial redox balance and protecting mitochondrial energy metabolism. In addition, our results uncover a novel mitochondrial mechanism underlying RSL3-induced oxidative stress and ferroptosis that can be modulated through targeted regulation of the ETC.

In addition, GA synergizes with RSL3, a GPX4 inhibitor, to promote ferroptosis in mutant p53 cancer cells in both cellular and animal studies. In summary, our findings identify GA as a promising compound that reactivates mutant p53 through thiol modification, restoring its wild-type function and inducing ferroptosis in p53-mutant cancer cells. The findings of this study establish a foundational rationale and new perspectives for a mutant p53-directed therapeutic paradigm in oncology.

Tumor-derived Cav-1 promotes ROS-dependent ferroptosis in MDSCs via PKA-DRP1-mediated ER-mitochondrial crosstalk, causing the release of oxidized phosphatidylcholines that suppress T-cell function and promote an immunosuppressive TME. Targeting this axis may improve the response of breast cancer patients to immunotherapy.