Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Dan Feng,Jian Zhang,Huanmin Niu,Xiaoxue Zheng,Mengqi Jia,Qiqi Lu,Jing Wang,Wenxue Guo,Qi Sun,Huiqing Yuan,Hongxiang Lou
The elevated polyamines, amine-rich molecules with diverse functions in pathophysiology processes, are implicated in contributing to tumorigenesis and progression. Whether and how they affect the efficacy of chemotherapy is incompletely understood. Our screening assays reveal that the supplement with a low dose of spermidine (Spd), one of the polyamines, enhances ferroptosis in prostate cancer cells as evidenced by increased lipid peroxidation and intracellular Fe 2+ levels in vitro . Combination treatment with Spd and a low dose of ferroptosis inducer erastin synergistically augments anti-tumor efficacy with undetectable toxicity in mice. Analysis of RNA-seq data indicates that heme oxygenase 1 (HMOX1), an enzyme that catalyzes the cleavage of heme to release Fe 2+ , is significantly upregulated in response to Spd and erastin cotreatment. Spd mediated the hypusine modification of the eukaryotic initiation factor 5A (EIF5A) promotes the translation of the nuclear factor erythroid 2-related factor 2 (NRF2), subsequently leading to elevation of HMOX1. Moreover, Spd and erastin significantly inhibit proteasome activity which results in a decrease in proteasomal degradation of NRF2, although many proteasome-related genes are induced either by Spd or Spd plus erastin. Thus, in addition to its pro-oncogenic activity, the supplement of Spd improves antitumor activity in combination with ferroptosis inducers and offers an optional approach to cancer treatment.
研究领域:
肿瘤学
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分子生物学
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药理学
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2026
·Vol. 58
·期 4
·1-19
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IF 8.5
Yuanyuan Yong,Yuxin Hu,Qian Feng,Xiaogang Zhou,Lu Yu,Dalian Qin,Jianing Mi,Jianming Wu,Jianxin Liu,Anguo Wu
International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.
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ACS Nano
·
2026
·
IF 17.3
Jinzhe Liang,Xianliu Luo,Ya-Qian Shi,Liang-Mei Yang,Caiying Li,Lixian Huang,Yuzhen Ma,Yong Huang,Shulin Zhao
Controlling ferroptosis through material redox dynamics represents a frontier in the field of catalytic nanomedicine. Here, we introduce nonstoichiometric bismuth ferrite (BiFeO3–x) as an H2S-activable semiconductor that couples oxygen-vacancy-enabled charge modulation with endogenous sulfur chemistry to achieve spatiotemporally controlled immunogenic ferroptosis. Upon exposure to tumor-enriched gasotransmitter H2S, BiFeO3–x undergoes a transformation into Bi2S3 while releasing Fe2+ ions to trigger Fenton-like lipid peroxidation. The material’s mixed-valence Fe redox pair amplifies reactive oxygen species generation under 808 nm excitation, coupling photothermal energy dissipation with catalytic ferroptotic stress. Biologically, this multiresponse process initiates mitochondrial collapse, glutathione peroxidase 4 depletion, and lipid peroxide accumulation, driving apoptosis–ferroptosis cascades. In vivo, photoacoustic-guided therapy and mass cytometry profiling reveal profound immune remodeling, such as dendritic cell maturation, CD8+ T cell infiltration, and M1 macrophage polarization, implying the conversion of “cold” colorectal tumors into immunogenic tumor microenvironments. This work establishes a defect-chemistry-oriented design framework for engineering redox-programmable nano semiconductors that translate lattice instability into biological selectivity, bridging ferroelectric materials science and immune oncology.
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高影响因子
Advanced Science
·
2026
·
IF 14.1
Menghao Qiao,Liqun Zhou,Minhua Zhou,Yu Fang,Haiying Mai,Lingbo Cao,Kun Xu,Yuan Sang,Minyi Chen,Jiewei Huang,Peiyi Huang,Zhipeng Yan,Chao Wang,Zhangshuai Dai,Dichun Huang,Ronghan He,Lijuan Pang,Yunmiao Guo,Ting Gang Chew,Junqi Huang
Ferroptosis is an iron-dependent form of programmed cell death governed by redox homeostasis. Although Ezrin, Radixin, and Moesin (ERM) proteins are established membrane-actin cytoskeleton linkers, their role in ferroptosis remains unexplored. Here, ERM proteins are identified as modulators of erastin-induced ferroptosis. In human fibrosarcoma HT-1080 cells, pharmacological inhibition of ERM phosphorylation, knockdown of individual ERM members, or overexpression of a phospho-deficient Ezrin mutant (T567A) consistently attenuated ferroptosis, whereas wild-type ERM overexpression enhances ferroptosis susceptibility. Mechanistically, ERM inhibition leads to F-actin depolymerization accompanied by a modest rise in reactive oxygen species (ROS). F-actin stabilization prevents this ROS surge and restores ferroptotic sensitivity, whereas its depolymerization mimics the protective effect of ERM inhibition. ROS elevation triggers KEAP1 degradation, stabilizing NRF2 and promoting its nuclear translocation. Activated nuclear NRF2 induces antioxidant genes, particularly HMOX1 , a key effector of heme catabolism that enhances redox buffering and limits lipid peroxidation, ultimately conferring resistance to ferroptosis. The protective effects of ERM inhibition are further validated in ferroptosis-relevant ex vivo and in vivo models. Notably, other pro-oxidants similarly attenuate ferroptosis at appropriate concentrations. Together, these results establish ERM proteins as regulators of ferroptosis and reveal an underappreciated group of ferroptosis inhibitors that engage ROS-NRF2-mediated redox-adaptation.
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高影响因子
Genes
·
2024
·Vol. 15
·期 10
·1316
·
IF 2.8
Ping Zhang,Na Qian,Haigen Lai,Shu Chen,Kuaiying Wu,Xiaofeng Luo,Bo Lei,Mengqi Liu,Jiajun Cui
Background: Estrogen receptor-positive breast cancer accounts for around 70% of all cases. Tamoxifen, an anti-estrogenic inhibitor, is the primary drug used for this type of breast cancer treatment. However, tamoxifen resistance is a major challenge in clinics. Metabolic reprogramming, an emerging hallmark of cancer, plays a key role in cancer initiation, progression, and therapy resistance. The metabolism of non-essential amino acids such as serine, proline, and glutamine is involved in tumor metabolism reprogramming. Although the association of glutamine metabolism with tamoxifen resistance has been well established, the role of proline metabolism and its critical enzyme PRODH is unknown. Objective: The aim of this study is to explore the role and mechanism of PRODH in tamoxifen resistance in breast cancer cells. Methods: PRODH and GPX4 expressions in tamoxifen-resistant cells were detected using real-time PCR and Western blot analysis. The breast cells’ response to tamoxifen was measured using MTT assays. Trans-well assays were used to detect cell migration and invasion. A Xenograft tumor assay was used to detect the role of PRODH in tumor growth. Reactive oxygen species were measured using flow cytometry. Results: PRODH expression is reduced in tamoxifen-resistant cells, and its overexpression enhances tamoxifen response in vitro and in vivo. Conversely, PRODH knockdown confers tamoxifen resistance in tamoxifen-sensitive cells. Mechanistic studies show that ferroptosis is inhibited in tamoxifen-resistant cells and overexpression of PRODH restores the ferroptosis in tamoxifen-resistant cells. Moreover, Ferrostatin-1 (Fer-1), the ferroptosis inhibitor, reversed the effect of PRODH on tamoxifen resistance. Conclusions: These findings suggest that PRODH regulates tamoxifen resistance by regulating ferroptosis in tamoxifen-resistant cells.
研究领域:
肿瘤学
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分子生物学
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癌症代谢
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药理学
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高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
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2025
·Vol. 30
·期 1
·1-27
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IF 10.2
Chen Dejian,Xie Fei,Mo Yimei,Qin Dan,Zheng Binjiao,Chen Lingyan
Background The classical ferroptosis activator RSL3 targets enzymes with nucleophilic active sites, primarily acting on glutathione peroxidase 4 (GPX4) to trigger ferroptosis. Recent studies identify RSL3 as a potential pro-apoptotic agent. However, the mechanism by which RSL3 induces apoptosis during ferroptosis remains elusive. Poly(ADP-ribose) polymerase (PARP1) determines cell fate in response to DNA damage, where its loss or cleavage by activated caspase-3 induces apoptosis to attenuate tumor progression. We elucidate a novel mechanism underlying PARP1 regulation, encompassing both its caspase-dependent cleavage and full-length depletion during RSL3-mediated ferroptosis-apoptosis crosstalk. Methods To investigate the role of RSL3 during ferroptosis, we treated several cancer cells of different histological types with varying doses of RSL3 to induce apoptosis. The regulatory proteins of PARP1 were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The N 6 -methyladenosine (m 6 A) modification level of PARP1 was determined by m 6 A RNA immunoprecipitation (MeRIP)-qPCR analysis. Additionally, an RNA immunoprecipitation (RIP)-qPCR assay was performed to identify the target protein of the m 6 A site of PARP1. Furthermore, we established a mouse xenograft model of PARP inhibitor (PARPi)-resistant cells to analyze the effect of RSL3 on PARPi-resistant tumor growth. Results RSL3 triggers two parallel apoptotic pathways via increasing reactive oxygen species (ROS) production during ferroptosis: (1) caspase-dependent PARP1 cleavage and (2) DNA damage-dependent apoptosis resulting from reduced full-length PARP1. The latter occurs through inhibition of METTL3-mediated m 6 A modification and subsequent suppression of PARP1 translation. Moreover, we found that RSL3 retains pro-apoptotic functions in PARPi-resistant cells and effectively inhibits PARPi-resistant xenograft tumor growth in vivo. Conclusions RSL3 orchestrates ferroptosis-apoptosis crosstalk via PARP1, demonstrating therapeutic potential against tumorigenesis, particularly in PARPi-resistant malignancies. Graphical
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ACS Nano
·
2025
·
IF 16
Tianshu Hao,Hanze Guo,Chenyuan Wang,Shisuo Jing,Wen Zhang,Yongnian Zeng,Jinxuan Hou,Zhiyin Song,Wei Li
Mitochondrial hyperfunction in doxorubicin (DOX)-resistant breast cancer cells mitigates oxidative stress, contributing to chemoresistance. Here, we present a precise mitochondria-targeted microneedle (MN) delivery strategy incorporating hollow DOX-TPP@ZIF-67 nanoparticles to overcome chemotherapy resistance. This platform was synthesized by loading mitochondria-targeted DOX-TPP into ZIF-67 structures and embedded into fast-dissolving MN patches for localized, organelle-specific drug delivery. Mitochondrial accumulation of DOX-TPP induces ROS overproduction, triggering apoptosis, disrupting cystine–cysteine conversion, depleting glutathione (GSH), and inactivating GPX4. The resulting oxidative imbalance promotes lipid peroxidation and ferroptosis. Additionally, the hydrogen peroxide generated during metabolic reprogramming drives further ferroptosis via the Fenton-like reaction. This approach effectively suppresses the growth of chemoresistant tumors and prolongs survival in DOX-resistant animal models. Our results demonstrate that mitochondria-targeted MN delivery provides a precise strategy to overcome chemoresistance and uncover a mechanism by which enhanced anthracycline efficacy drives the synergistic activation of mitochondrial dysfunction, apoptosis, and ferroptosis.
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高影响因子
CHEMICAL ENGINEERING JOURNAL
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2025
·
IF 13.2
Gao He,Xiafei Yu,Junzhe Yang,Lile Dong,Jialu Xu,Xian Wu,Xiang Li,Xiaoan Liu
Ferroptosis has emerged as a promising strategy for enhancing tumor immunogenicity. However, a major obstacle to the efficacy of ferroptosis-based immunotherapy is the immunosuppressive tumor microenvironment, particularly the dominance of tumor-associated macrophages (TAMs) exhibiting the M2 phenotype. These M2 macrophages secrete immunosuppressive factors, limiting the therapeutic potential of ferroptosis. To overcome these challenges, hollow Te/PtTe 2 inducers were designed to enhance immunotherapy induced by ferroptosis. The unique hollow structure of Te/PtTe 2 inducers effectively captures mechanical energy, promotes efficient electron-hole separation, and triggers reactive oxygen species (ROS) storms within tumor cells. Simultaneously, Te/PtTe 2 inducers synergistically deplete intracellular GSH in combination with ROS storm effects, triggering ferroptosis and releasing damage-associated molecular patterns, enhancing tumor immunogenicity. Additionally, Te/PtTe 2 inducers reshape the immunosuppressive microenvironment under US irradiation by increasing mature dendritic cells, promoting CD8 + T cell infiltration, and reducing immunosuppressive M2 macrophages. Collectively, this work provides a piezoelectric enhancement strategy to overcome immunosuppressive barriers and improve the clinical effectiveness of ferroptosis in cancer treatment.
研究领域:
生物医学
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肿瘤学
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免疫学
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材料科学与医学应用
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高影响因子
INFLAMMATION RESEARCH
·
2025
·Vol. 74
·期 1
·1-20
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IF 5.4
Song Chao,Shen Baoxin,Chen Chaoqi,Yang Lei,Zhang Chi,Liu Fei,Chen Feng,Wu Xiaofei
Background Osteoarthritis (OA) is a common chronic degenerative joint disease in orthopedics, and ferroptosis is a newly identified mode of cell death present in OA. Inhibition of inflammatory cytokine expression and modulation of chondrocyte ferroptosis related pathways may be novel strategies for the treatment of OA. The purpose of this work was to uncover prospective biomarkers and molecular processes of ferroptosis in OA, as well as to better understand the molecular mechanisms of ferroptosis in OA treated with resveratrol. Material and methods We obtained OA gene expression profiles from the Gene Expression Omnibus (GEO) database. OA-expressed ferroptosis-related genes were identified using Genecards data, differential gene analysis, and weighted gene co-expression network analysis. Enrichment analysis was utilized to identify signaling pathways and molecular mechanisms linked with ferroptosis in OA, while immune infiltration analysis indicated immune cell infiltration in OA. The action targets of resveratrol were taken from the TCM database to determine the therapeutic targets of resveratrol for the treatment of OA. To validate the molecular process, molecular docking was performed using the therapeutic targets' enrichment analysis. Finally, in vitro investigations confirmed the molecular mechanism of ferroptosis in resveratrol-treated OA. Results Bioinformatic analysis identified 462 OA ferroptosis gene sets, with GPX4, TFRC, SLC7A11, EGFR, and IL1B serving as significant hub genes. Enrichment analysis revealed that ferroptosis was also linked to animal mitophagy, the FoxO signaling pathway, the Toll-like receptor signaling pathway, the PI3K-Akt signaling pathway, inflammation, immune response activation, and cellular autophagy. The immune infiltration data revealed that T_cells_CD4_memory_resting, T_cells_CD4_memory_activated, NK_cells_activated, and Mast_cells_activated were considerably infiltrated in OA. Resveratrol ameliorated OA via modulating autophagy and ferroptosis via GPX4, TFRC, SLC7A11, EGFR, and IL1B, according to a mechanistic study. Conclusion We discovered the mechanism of GPX4, TFRC, SLC7A11, and EGFR, IL1B ferroptosis-related genes in OA, and preliminary evidence suggests that resveratrol improves OA by regulating ferroptosis and immunological processes, which may give a new route for OA treatment.
研究领域:
医学
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生物信息学
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高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2026
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IF 14.3
Jia-Rui Du,Mu-Le Tu,Yong-Xu Xia,Yuan-Qiang Lin,Rui Yang,Chang Weng,Yi Liu,Hao Zhang,Hui Wang,Wen-Jie Feng,Deng-Ke Teng
Nanovaccines based on immunogenic cell death (ICD) present a promising strategy in tumor immunotherapy, serving as a bridge connecting tumor cell death to the induction of anti-tumor immunity. However, their efficacy is severely limited by the immunologically silent nature of apoptosis-dependent ICD and the immunosuppressive tumor microenvironment (TME). In this work, we designed a metal‒polyphenol network nanovaccine (SRF@FeShik-cGAMP/HA). Upon reaching the tumor tissue through specific targeting, the nanovaccines disassemble within the tumor cells, releasing the Fenton reaction catalyst ferrous iron (Fe 2+ ), the system Xc- inhibitor sorafenib (SRF), and necroptosis inducer shikonin. Fe 2+ , SRF, and shikonin collectively promote the accumulation of lipid peroxide and amplify ferroptosis by providing an exogenous iron source, inhibiting glutathione biosynthesis, and boosting reactive oxygen species production, respectively. Meanwhile, shikonin induces necroptosis. The combination of ferroptosis and necroptosis overcomes the limitation of tumor immune silencing and triggers a strong ICD. Simultaneously, the immune adjuvant 2'3'-cyclic-GMP-AMP (cGAMP) activates the STING pathway, reversing the immunosuppressive TME and enhancing the anti-tumor immune response mediated by ICD. The synergistic action of ferroptosis, necroptosis, and the STING pathway produces a cascade of antitumor immune responses and establishes long-term immune memory. This nanovaccine demonstrates promising therapeutic effects in primary, orthotopic, and recurrent hepatocellular carcinoma (HCC) models. Collectively, our findings present a cancer immunotherapy strategy that exploits dual ferroptosis and necroptosis induction to trigger ICD, bypassing the limitations of apoptosis-dependent pathways. This strategy coordinates with the STING pathway to achieve potent antitumor immunity, providing a promising paradigm for HCC treatment, and offering a promising and translatable path for clinical development.
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高影响因子
Frontiers in Oncology
·
2021
·
IF 6.244
Yuan Yin,Ni Shuo,Zhuge Aoxiang,Li Bo,Li Lanjuan
Iron promotes the proliferation of cancer cells, but it also contributes to cell death. Here we explored whether iron could promote the Warburg effect of colorectal cancer (CRC) cells and suppress sensitivity to ferroptosis by inducing reactive oxygen species (ROS) and regulating nuclear factor erythroid 2-related factor 2 (NRF2). In this study, cell proliferation abilities were measured by CCK-8, EdU incorporation, and colony formation assays. Seahorse XF96 respirometry assays were used to detect the Warburg effect and the level of ROS was assess by DCFH-DA fluorescent probes. Results showed that iron exposure promoted the Warburg effect of CRC cells by inducing ROS and activating NRF2 both in vivo and in vitro. In addition, iron exposure also induced ferroptosis in CRC cells, but at the same time its inhibitory proteins SLC7A11 and GPX4 were also upregulated, indicating an enhanced resistance to ferroptosis. Our results revealed that iron can effectively promote tumorigenesis. Meanwhile, iron elimination or a low-iron diet might be valid therapeutic approaches for CRC.
研究领域:
肿瘤学
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细胞生物学
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分子生物学
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高影响因子
ACS Applied Bio Materials
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2022
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IF 0
Xiangrong Tian,Li Ruan,Shengwang Zhou,Lin Wu,Jin Cao,Xueyong Qi,Xin Zhang,Song Shen
Iron oxide nanoparticles can induce cell death due to the ferroptosis mechanism, showing a great potential for cancer therapy. Here, we synthesized different-sized iron oxide nanoparticles (2–100 nm) to investigate their antitumor effect and toxicity mechanism. It was found that ultrasmall nanoparticles (< ∼5 nm) could accumulate in nucleus and were more efficient in triggering the generation of •OH than larger nanoparticles due to the quicker release of Fe2+, thus exhibiting more remarkable cytotoxicity. Nevertheless, 10 nm iron oxide nanoparticles group displayed the best antitumor effect in vivo. We studied the in vivo and intratumoral biodistribution of the nanoparticles and found that the therapeutic effects were related to both the tumoral accumulation and intratumoral distribution of nanoparticles. This work indicates the appropriate size of Fe3O4 NPs for cancer treatment and illustrates the possible factors that influence the therapeutic effect, suggesting the great potential of iron oxide in clinical application.
研究领域:
生物医学工程
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肿瘤学
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纳米医学
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