INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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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
·
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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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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INFLAMMATION RESEARCH
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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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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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CHEMICAL ENGINEERING JOURNAL
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2025
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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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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Xingyu Chen,Wenqian Sun,Yanting Song,Shangong Wu,Shouqi Xie,Wen Xiong,Chengdong Peng,Yu Peng,Zhengxiang Wang,Sovan Lek,Christer Hogstrand,Mette Sørensen,Lei Pan,Dong Liu
The impact of cadmium (Cd) toxicity on fish liver injury has received much attention in recent years. Currently, autophagy, apoptosis and endoplasmic reticulum stress were reported in Cd exposed fish liver, and if there are other mechanisms (such as ferroptosis) and relevant signaling pathways involved in fish remains unknown. An experiment was conducted to investigate Cd toxicity in Channa argus (Cantor, 1842) exposed to 0, 1.0, and 2.0 mg Cd/L of water for 96 h. Cd disrupted the structure of mitochondria in the liver. Besides, Cd induced ferroptosis by significantly increasing the level of Fe 2+ , ROS, MDA and significantly decreasing the level of Ferritin, GSH, GSH-Px, GPX4, GST and SOD ( p < 0.05 in all cases). In addition, the mRNA expression of ferroptosis related genes, gpx4 and slc7a11 , were significantly downregulated by Cd. Moreover, Cd exposure significantly inhibited the Nrf2/Keap1 signaling pathway, one of the pathways involved in ferroptosis, by upregulating the mRNA levels of keap1a and keap1b , and downregulating the mRNA levels of nrf2 and its target genes ( ho-1 , nqo1 and cat ). Cd exposure also caused extensive accumulation of vacuoles and lipid droplets in liver, as well as an increase in triglyceride content. Cd significantly affected lipid metabolism related enzyme activity and gene expression, which were also regulated by Nrf2/Keap1 signaling pathway. In summary, these results indicate that ferroptosis is a mechanism in waterborne Cd exposed fish liver injury via the Nrf2/Keap1 signaling pathway and the Cd induced hepatic steatosis is also modulated by Nrf2/Keap1 pathway at the whole-body level in fish. These findings provide new insights into the fish liver injury and molecular basis of Cd toxicity.
研究领域:
环境毒理学
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鱼类生理学
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分子生物学
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高影响因子
JOURNAL OF GENE MEDICINE
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2024
·Vol. 26
·期 10
·e3742
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IF 3.2
Fuyun Zhu,Dezeng Zou,Ping Shi,Lianhua Tang,Dan Wu,Xiaoxue Hu,Fei Yin,Jianhui Liu
Background With its rapidly increasing incidence and prevalence, ulcerative colitis (UC) has become a major global health challenge. Recent evidence suggests that ferroptosis plays a significant role in the development of UC. However, the relationship between ferroptosis and the progression of UC needs to be extensively studied. Methods The differentially expressed genes in UC patients were screened from the GEO database. The ferroptosis-related genes were obtained from FErrDB and GeneCards. The UC subtypes were identified with the R package “CancerSubtype” and evaluated with consensus clustering (CC) to identify gene expression patterns in patients with UC. The key genes were detected with qRT-PCR, Western blot, and immunohistochemistry in vitro and in vivo models. Ferroptosis was identified with western blotting on ferrotic-associated proteins and staining on Fe 2+ with commercial FerroOrange kits. Results Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a potential biomarker for ferroptosis in UC patients. Transcriptome sequencing data showed a positive correlation between decreased DPP4 expression and proinflammatory cytokines such as TNF-α, IL-6, and IL-β, as well as immune cell infiltration in the colon tissues of UC patients. Furthermore, DPP4 was strongly associated with ferroptosis biomarkers, particularly in Subtype 2 of UC. Interestingly, our study also found that DPP4 expression was significantly reduced in RSL3-treated ferroptotic intestinal epithelial cells, more so than in LPS-treated cell models. Inhibition of DPP4 had a significant impact on the expression of ferroptotic biomarkers. Additionally, DPP4 expression was decreased in the colon tissues of DSS-treated mice, and the ferroptosis inhibitor Ferritin-1 effectively counteracted the effects of DSS on immune cell infiltration, colon length, and DPP4 expression. Conclusions DPP4 can serve as a biomarker for ferroptosis in the diagnosis and management of UC. Highlights DPP4-mediated ferroptosis is involved in ulcerative colitis DPP4 is a novel diagnostic biomarker of ulcerative colitis Ferroptosis involves intestinal epithelial cell death in ulcerative colitis
研究领域:
胃肠病学
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分子生物学
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免疫学
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药理学
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JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Lipeng Zhu,Dongliang Leng,Ziang Guo,Yuetao Zhao,Kam-Tong Leung,Yeneng Dai,Junnan Li,Qi Zhao
Ferroptosis, triggered by membrane lipid peroxidation (LPO) and diminished antioxidants, can be induced by intracellular iron (II, Fe 2+ ). However, the role of nitric oxide (NO) in causing Fe 2+ overload for ferroptosis remains uncertain. This study reveals that NO can stimulate endogenous Fe 2+ release by upregulating heme oxygenase 1 (HMOX1) expression. Here, ferritin heavy chain (FHC) siRNA and hyaluronic acid (HA)-modified Arg-stabilized zinc peroxide (AZOSH), a non-ferrous-based nanoagent, is synthesized to trigger ferroptosis by inducing intracellular Fe 2+ overload. AZOSH, a self-catalyzed NO nanocomplex, effectively generates NO through a reaction of self-supplied Arginine (Arg) and hydrogen peroxide (H 2 O 2 ), which promotes glutathione (GSH) consumption to downregulate glutathione peroxidase 4 (GPX4) expression and produces peroxynitrite (ONOO − ) to enhance LPO. Meanwhile, NO promotes endo/lysosomal escape of siRNA by damaging membrane structures. Moreover, AZOSH significantly triggers Fe 2+ overload through the synergistic effects of NO-activated HMOX1 expression and FHC siRNA-mediated ferritin sequestration. Additionally, the released Zn 2+ from AZOSH induces oxidative stress by inhibiting mitochondrial function, further promoting ferroptosis. Consequently, AZOSH-mediated ferroptosis exhibits a strong cellular immunogenic response for T-cell activation and infiltration. Importantly, the integration of AZOSH with an anti-PD-1 antibody results in notable antitumor efficacy in vivo . Therefore, this study provides a novel concept of NO-induced ferroptosis, highlighting its role in enhancing PD-1-based immunotherapeutic efficacy.
研究领域:
癌症生物学
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免疫学
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分子生物学
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治疗学
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BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Yu Shi,Yi Zhao,Si-Jia Sun,Xiu-Ting Lan,Wen-Bin Wu,Zhen Zhang,Yu-Xin Chen,Yu-Ying Yan,Yu-Ping Xu,Dong-Jie Li,Hui Fu,Fu-Ming Shen
Abdominal aortic aneurysm (AAA) is a potentially fatal cardiovascular disease, closely related to inflammation and loss of vascular smooth muscle cells (VSMCs). Ferroptosis is an iron-dependent cell death associated with peroxidation of lipids. However, the direct role of glutathione peroxidase 4 (GPX4) itself determined ferroptosis in the course of AAA pathogenesis remains unknown. Here, we reported that ferroptosis was triggered in human AAA, elastase- and angiotensin II (Ang II)-induced mouse AAA, and Ang II-incubated VSMCs. Inhibition of ferroptosis via global genetic overexpression of GPX4, a critical anti-ferroptosis molecule, markedly prevented both vascular remodeling and inflammatory response. Mechanistically, GPX4 changed the migration and activation of macrophages/monocytes in AAA tissues in mice. Experiments in vitro demonstrated that overexpression of GPX4 prevented the JAK1/STAT3 signaling activation in VSMCs induced by IL-6, production of pro-inflammatory macrophages. Finally, the role of ferroptosis was confirmed on an Ang II-induced mice AAA model. These results emphasized the significance of ferroptosis in AAA, and provided novel insights that therapy focusing on GPX4 might be a promising strategy for treatment of AAA in the clinic.
研究领域:
心血管疾病
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分子生物学
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CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Huilan Zhuang,Lun Wang,Sijie Shao,Haitong Jing,Panpan Xue,Tingjie Bai,Jinpeng Deng,Xuemei Zeng,Xian Qin,Shuangqian Yan
Ferroptosis has emerged as a novel approach to suppress tumor growth through the iron-dependent accumulation of lipid peroxides, providing new opportunities for cancer therapy. However, the effectiveness of ferroptosis is impeded by the substantial neutralization of reactive oxygen species (ROS), generated through the Fenton reaction, by the high level of glutathione in cancer cells. Here we report a titanium metal–organic frameworks (MOFs)-derived method to create black TiO 2 nanoparticles with excellent photocatalytic performance. The nanoparticle has a narrow bandgap of 1.02 eV, multiple discrete gap states, and a high density of oxygen vacancies (46.2 %), facilitating ROS generation under 1064-nm light irradiation. When coated with a tannic acid/Fe 3+ layer, the resulting nanocomposite possesses the ability to deplete glutathione concentration, preventing the newly generated ROS from being neutralized and promoting ferroptotic cancer cell death. Complemented by photothermal and chemodynamic effects, in vivo experiments demonstrate a high tumor inhibition rate of 89.8 %. The utilization of MOF-derived nanomaterials represents a universal strategy, offering a solution for ferroptosis-based therapy in solid tumors and contributing to the development of smart, optically active materials with diverse applications in biological contexts.
研究领域:
生物医学
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材料科学
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肿瘤学
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高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2024
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IF 9.4
Deyan Gong,Lu Liu,Ziwen Xiao,Zhuonan Yang,Yaoyu Hu,Taikui Sheng,Yajing Liu,Zhaohua Miao,Zhengbao Zha
Nanozymes have made great achievements in the research of tumor therapy. However, due to the complex tumor microenvironment, the catalytic activity and biosafety of nanozymes are limited. High catalytic efficiency is a relentless pursuit for the preparation of high-performance nanozymes. Dimensional reduction from 3D nanoscale metal–organic frameworks (nMOFs) to 2D nanoscale metal–organic layers (nMOLs) increases the encounters frequency of nanozymes and substrate, which facilitates the diffusion of reactive oxygen species (ROS) from nMOLs, thus significantly improving the effectiveness of chemodynamic therapy. In this study, He@Ce-BTC nMOF and He@Ce-BTB nMOL based on Ce 6 SBUs were synthesized by solvothermal reaction. Compared with the 3D nMOFs, the 2D nanozymes He@Ce-BTB nMOL possessed enhanced ROS catalytic efficiency, were able to be activated by the tumor acidic microenvironment with the polymerase mimetic activities (CAT, POD, GSH-OXD) that enhances the lipid peroxidation process and accelerates the process of ferroptosis thereby killing tumor cells. In addition, He@Ce-BTB does not affect normal tissue cells, thus avoiding diffusion-induced side effects. He@Ce-BTB has shown excellent therapeutic effects in vitro and in vivo , which indicates its potential for clinical application, and is expected to become a new generation of drugs for the treatment of tumors.
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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高影响因子
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