INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Hongzi Wu,Bowen Li,Jichun Shao,Qingquan Kong
The clinical use of chemotherapy for refractory osteosarcoma (OS) is limited due to its multiorgan toxicity. To overcome this challenge, new dosage forms and combination treatments, such as phototherapy, are being explored to improve targeted delivery and cytocompatibility of chemotherapeutic agents. In addition, inducing ferroptosis in iron-rich tumors could be a promising strategy to enhance OS therapy. In this study, a novel formulation was developed using natural biological H-ferritin (HFn) encapsulating the photosensitizer IR-780 and the chemotherapy drug gemcitabine (Gem) for OS-specific targeted therapy (HFn@Gem/IR-780 NPs). HFn@Gem/IR-780 NPs were designed to specifically bind and internalize into OS cells by interacting with transferrin receptor 1 (TfR1) which is overexpressed on the surface of OS cell membranes. The Gem and IR-780 were then released responsively under mildly acidic conditions in tumors. HFn@Gem/IR-780 NPs achieved cascaded antitumor therapeutic efficacy through the combination of chemotherapy and phototherapy under near-infrared irradiation in vitro and in vivo . Importantly, HFn@Gem/IR-780 NPs demonstrated excellent safety profile with significantly decreased drug exposure to normal organs, indicating its potential for reducing systemic toxicity. Thus, utilizing HFn as a vehicle to encapsulate highly effective antitumor drugs provides a promising approach for the treatment of OS metastasis and relapse.
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JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·713
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IF 12.6
Zhou Hongmei,Liang Yujia,Liu Lijuan,Liang Yulin,Tang Jiaying,Ding He,Ning Shufang,Yang Piaoping,Wang Chen
Background Ferroptosis, a programmed cell death driven by lipid peroxidation, relies on an oxidative imbalance. However, tumor cells counteract the effects of oxidative imbalance through adaptive defense mechanisms and metabolic reprogramming, thereby limiting the therapeutic efficacy of ferroptosis. Results An antitumor strategy was designed to synergistically induce ferroptosis and apoptosis by targeting the release of nitric oxide (NO) and zinc ions (Zn 2+ ), effectively disrupting the redox homeostasis and antioxidant capacity of tumor cells. ZIF-8 degradation in tumor cells triggers Zn 2+ -mediated mitochondrial electron transport chain inhibition and nicotinamide adenine dinucleotide phosphate oxidase 1 activation, significantly increasing endogenous reactive oxygen species (ROS) levels. NO-derived reactive nitrogen species exhibit strong oxidative activity, amplifying ROS-mediated oxidative imbalance, and promoting lipid peroxidation by depleting glutathione and inhibiting glutathione peroxidase 4 activity, inducing ferroptosis and apoptosis. Furthermore, NO disrupts intracellular redox equilibrium by activating endoplasmic reticulum stress and inhibiting the mitochondrial electron transport chain, resulting in calcium overload and mitochondrial malfunction. Conclusions Multi-pathway disruption of intracellular adaptive defense mechanisms and metabolic reprogramming homeostasis can be achieved via NO synergistic Zn 2+ , offering the potential for developing highly effective combined ferroptosis and apoptosis antitumor therapies. Graphical abstract
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Nature Communications
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2025
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IF 15.7
Wang Yanqiu,Tan Lu,Yang Yi,Duan Hongli,Liu Chao,Zhao Jing,Zhou Yue,Li Changqing,Liu Minghan
Intervertebral disc degeneration is a major cause of low back pain and is driven by a vicious cycle of reactive oxygen species (ROS), ferroptosis, and inflammation, afflicting millions of people worldwide. Breaking this cycle represents a significant therapeutic challenge. Here, we develop a ROS-responsive hydrogel loading a resident nanozyme system composed of nucleus pulposus cell membrane-coated black phosphorus@cerium oxide to disrupt this degenerative cascade. Specifically, the nanozyme exhibits a self-sustaining cerium redox cycle due to the incorporation of black phosphorus nanosheets into cerium oxide, conferring durable antioxidant capacity for scavenging ROS. Furthermore, it suppresses the inflammatory cytokine IL6 by inhibiting HuR-mediated mRNA stabilization, thereby blocking the pro-inflammatory and pro-ferroptotic IL6/STAT3 axis. Together, this dual mechanism enables our nanozyme-functionalized hydrogel to break the ROS-ferroptosis-inflammation feedback loop, thus effectively promoting structural and functional disc repair.
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ACS Applied Materials & Interfaces
·
2025
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IF 8.2
Jing Xu,Danyi Shen,Yao Wang,Xingyue Han,Xinning Dong,Xin Chen,Haifeng Shu,Jianwen Hou,Sixun Yu
Traumatic brain injury (TBI) can trigger a series of complex physiological responses, with iron overload and neuronal ferroptosis playing particularly pivotal roles. These processes exacerbate secondary brain injury and significantly deteriorate neurological function. To address this challenge, this study developed an innovative local drug delivery strategy: an injectable, post-traumatic microenvironment-responsive hydrogel. The hydrogel, composed of tannic acid (TA) and quaternized chitosan (QCS), is designed to alleviate neurological deficits secondary brain injury following TBI through its anti-ferroptosis mechanism. In vitro, a ferroptosis model was established using HT22 cells treated with the ferroptosis inducer RSL-3, demonstrating the hydrogel’s antioxidant capacity in the TBI-like conditions. The results showed that the hydrogel significantly restored cell viability, reversed iron accumulation, alleviated lipid peroxidation, and restored mitochondrial function. Further in vivo experiments in the TBI model showed that the TA/QCS hydrogel not only effectively inhibited neuronal degeneration, reduced iron accumulation, and lipid peroxidation but also restored mitochondrial function in neurons. Additionally, the hydrogel significantly attenuated neuroinflammation by inhibiting the activation of microglia and astrocytes, thereby facilitating neurological recovery after TBI. This study offers novel insights into TBI management strategies aimed at preventing the progression of a secondary injury.
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PHYTOMEDICINE
·
2022
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IF 6.656
Weiqi Cui,Junwei Zhang,Deqiao Wu,Jingxian Zhang,Hui Zhou,Ying Rong,Fanglin Liu,Bo Wei,Xia Xu
Background Pancreatic cancer is one of the most common malignant tumors of the digestive tract. Ponicidin, a tetracyclic diterpenoid active ingredient extracted from the traditional phytomedicine Rubescens, has high safety and great inhibitory effect on the proliferation of a variety of cancer cells, especially malignant tumor cells of the digestive tract. However, the inhibitory effect and mechanism of ponicidin on pancreatic cancer cells is still unclear. Our study aimed to use metabonomics technology to analyze and explore the suppressive effect of ponidicin against pancreatic cancer cells. Methods MTT and flow cytometry were conducted to study the potential effect of ponicidin on SW1990 cells. Secondly, UPLC-MS/MS was used to analyze the small molecule metabolites and relevant differential metabolic pathways induced by ponicidin treatment. Furthermore, through the determination of glutathione peroxidase 4 (GPX4) activity and molecular docking simulation experiments, the effects of intracellular GPX4 activity and GSH/GSSG ratio after ponicidin were evaluated. Finally, the determination of the content of iron ions and malondialdehyde in cells, and the experiment of the effect of ferroptosis inhibitors on cell viability, the effect of ponicidin on the induction of ferroptosis in SW1990 cells was also detected. Results The IC 50 of ponicidin on SW1990 cells was 20 μM, which could significantly induce cell apoptosis and arrest the cells in G 2 /M phase. Metabolomics results showed that the contents of endogenous small molecules such as gamma-glutamylcysteine, 5-oxoproline, glutamic acid, reduced glutathione (GSH), oxidized glutathione (GSSG) and arachidonic acid have changed significantly. Main differential compounds were involved in the gamma-glutamyl cycle and polyunsaturated fatty acid metabolism of pancreatic cancer cell lines. Additionally, ponicidin could covalently bind to GSH in SW1990 cells to form a conjugate Pon-GSH, which further reduced the content of free GSH and GPX4 activity in cells. Notably, ponicidin dose-dependently increased levels of iron ions, malondialdehyde and reactive oxygen species in SW1990 cells, and the ferroptosis inhibitors could significantly block the effects of ponicidin on the proliferation of SW1990 cells. Conclusion Ponicidin could suppress the pancreatic cancer cell proliferation via inducing ferroptosis by inhibiting the gamma-glutamyl cycle and regulating the polyunsaturated fatty acid metabolism in SW1990 cells.
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JOURNAL OF BIOLOGICAL CHEMISTRY
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2025
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IF 3.9
Mengna Zhu,Lin Huang,Si Sun,Mengqing Chen,Jing Cai,Yuan Zhang,Lufang Wang,Liqiong Cai,Minggang Peng
Platinum-based chemotherapy remains the cornerstone of the treatment of epithelial ovarian cancer (EOC); however, platinum resistance is a major cause of tumor recurrence and mortality in EOC patients. This study reports the mechanism by which EOC cells develop resistance to cisplatin by inhibiting the ferroptosis. Immunohistochemical analysis of human EOC tissues revealed that low p27 expression significantly correlated with poor response to chemotherapy and unfavorable patient prognosis. Functionally, CRISPR/Cas9-mediated p27 knockout increased cisplatin resistance in EOC cells in both in vitro and in vivo models. RNA sequencing and functional assays demonstrated that p27 enhanced cisplatin sensitivity by facilitating drug-induced ferroptosis in EOC cells. Mechanistically, luciferase reporter assays demonstrated that p27 enhanced the transcriptional activity of cytochrome b-245 heavy chain (CYBB), a key positive regulator of ferroptosis. Moreover, we found that the small molecule inhibitor SKPin C1 significantly enhanced cisplatin’s antitumor effect by preventing p27 degradation, both in vitro and in vivo . In conclusion, our findings emphasize the critical role of p27 in triggering ferroptosis, thereby sensitizing EOC cells to cisplatin therapy. These results suggest that therapeutic strategies aimed at enhancing p27 levels may represent a promising approach to overcoming chemoresistance in EOC.
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BIOORGANIC CHEMISTRY
·
2021
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IF 5.275
Xiuhan Guo,Haoze Yu,Wanjie Shen,Rui Cai,Yueqing Li,Guangzhe Li,Weijie Zhao,Shisheng Wang
Photodynamic therapy (PDT) is a non-invasive treatment method for tumors by exciting photosensitizers (PS) upon light irradiation to generate cytotoxic reactive oxygen species (ROS). However, the low oxygen concentration near the tumor tissue limits the therapeutic effect of PDT. Herein, we synthesized six chlorin e6 derivatives containing NO-donors to enhance their antitumor activity by synergistic effect of ROS and NO. The results revealed that the new NO-donor containing photosensitizers (PS-NO) exhibited more potent photodynamic activity than chlorin e6, and the introduction of NO donor moieties to chlorin e6 increased the level of NO and ROS in cells. The addition of Ferrostatin-1, a ferroptosis inhibitor, markedly reduced the photodynamic activity of PS-NO as well as the level of NO and ROS in cells. Mechanism studies further showed that PS-NO could reduce intracellular GSH level, inhibit GPX4 activity and promote malondialdehyde (MDA) accumulation upon light irradiation, which suggested the ferroptosis mechanism underlying the PDT effect of PS-NO.
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PHYTOTHERAPY RESEARCH
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2025
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IF 6.3
Ning Han,Liu-Gen Li,Mei-Yi Liu,Tao Ren,Yao-Hua Lu,Xing-Chun Peng,Cunqing Kong,Fan Leng,Lei Zhang,Jun Hu,Lei Wang,Tong-Fei Li,Mei-Fang Wang,Xiao Chen
Harringtonine (HT) is an alkaloid extracted from the botanical cephalotaxus fortunei Hook.f ., which has potent anti-tumor activity. Nevertheless, the target and mechanism of HT in cancer have not been reported. The present work aims to explore the crucial target of HT in triggering ferroptosis and elucidate its mechanism. Lewis lung cancer cells and tumor-bearing mice models prepared thereof were used in this study. Network pharmacology and RNA sequencing were utilized to screen the pivotal target and information. Flow cytometry, Western blots, qRT-PCR, and immunoprecipitation were exploited to elucidate the mechanism. The affinity experiments were employed to analyze the interaction of HT and FASN. Reduced cell viability and increased apoptosis were observed in HT-treated lung cancer cells and the 3-D cell model. Consistently, HT exhibited pronounced anti-cancer effects in in vivo experiments. The interaction molecules of HT and lung cancer were enriched in ferroptosis, which was validated by the accumulation of ferrous ions etc. Blockage of ferroptosis mitigated HT-mediated efficacy. Further investigation showed alternations in fatty acid metabolism when adding HT, especially fatty acid synthase (FASN). HT was demonstrated to bind to FASN, thereby dampening SYVN1-mediated ubiquitination. Finally, the silence of FASN dampened the ferroptosis and anti-cancer efficacy introduced by HT. Collectively, HT could bind to FASN and thereby enhance the activity by reducing ubiquitination, resulting in increased fatty acid synthesis and infiltrating into the membrane, which leads to ferroptosis. The present work identifies the critical target for phytomedicine HT-driven ferroptosis and provides a foundation for cancer therapy.
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Cell Death & Disease
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2025
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IF 9.6
Huang Hongli,Chai Yihan,Wu Xuewei,Wang Sen,Li Binglin,Wang Yanyan,Zheng Wen,Wu Yuefeng,Meng Di,Wang Hua,Tu Zhengliang,Du Chengli,Lyu Xiayi,Li Guiying,Guo Wei
Non-genetic resistance of cancer remains poorly understood in clinical research and practice. To better understand resistant cancer cell heterogeneity, we isolated a novel riboflavin + NOTCH1 + population from cisplatin-naïve and -resistant lung cancer cell lines and patient specimens with or without immunotherapy and chemotherapy. This population was also identified as SLC52A2 (one of the riboflavin transporters) + NOTCH1 + cells in single-cell RNA sequencing (scRNA-seq) data derived from advanced lung tumors before therapy. Despite its therapy-naïve origin, the population, designated as stably resistant cancer cells (SRCC), exhibited the epithelial state, innate and stable resistance to therapy (chemotherapy, targeted therapy and immunotherapy), cell dormancy, elevated reactive oxygen species (ROS), and anti-apoptotic and anti-ferroptotic survival. These cellular and molecular characteristics distinguished SRCC from other resistant populations, including cancer stem-like cells (CSC), epithelial-mesenchymal transition (EMT) cells, and drug-tolerant persisters (DTP). The non-canonical NOTCH1 pathway, but not the inactivated canonical NOTCH1 pathway, played a critical role in the resistance of SRCC. Specifically, it modulates cell cycle, iron metabolism, EMT, and ferroptosis vulnerability in SRCC at the transcriptional level. It also controls the initiation of ferroptosis in lysosomes via a posttranslational NOTCH1-AKT-BAX axis. Inhibition of the non-canonical NOTCH1 pathway re-sensitizes these dormant and resistant cells to cisplatin-induced cell death in vitro and in vivo, including ferroptosis, apoptosis, and necroptosis. Our study contributes to a deeper understanding of cancer resistance and promotes the development of more effective therapeutic strategies against resistant cancer cells.
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高影响因子
ONCOLOGY RESEARCH
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2025
·Vol. 34
·期 1
·26
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IF 4.1
Jianfa Wu,Huang Chen,Sihong Wang,Lei Peng,Xiaoying Hu,Zhou Liu
Objectives Ribosomal protein S6 kinase A2 (RPS6KA2) has been identified as a potential prognostic biomarker in several cancers, including breast cancer, glioblastoma, and prostate cancer. However, its functional significance in ovarian cancer is not well characterized. This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer, particularly in relation to cisplatin resistance. Methods The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR, immunofluorescence staining, immunohistochemistry, and western blotting. Prognostic associations were conducted using the Kaplan-Meier Plotter database. Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity. Ferroptosis-related parameters, including intracellular iron content, glutathione (GSH) levels, reactive oxygen species (ROS) generation, and mitochondrial membrane potential, were measured to determine ferroptotic changes. In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents. Results Using ovarian cancer cell lines and clinical tissue samples, we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts. Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance. Mechanistically, RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) signaling pathway, which in turn increased sensitivity to cisplatin. Additionally, RPS6KA2 facilitated ferroptosis, contributing to its tumor-suppressive function. miR-512-3p was identified as a negative regulator of RPS6KA2, driving cisplatin resistance through suppression of RPS6KA2 expression. In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models. Conclusion These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.
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JOURNAL OF INVESTIGATIVE MEDICINE
·
2023
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IF 2.6
Jun-Dong Lu,Mei-Lin Sun,Pei-Li,Xiao-Peng Wang
Local ischemia in the cerebra leads to vascular injury and necrosis. Ferroptosis is involved in the pathophysiological process of many diseases and widely exists when ischemia-reperfusion injury occurs in many organs. The aim of this study was to evaluate the effect of Butylphthalide (NBP) on middle cerebral artery occlusion (MCAO) rats model-caused neuron injury. Sprague Dawley Rats were randomly allocated to receive sham and MCAO operation. NBP low-dose (40 mg/kg b.w), and high-dose (80 mg/kg b.w) were administrated in MACO rats. Results showed NBP improves infarct volume, attenuates neuronal apoptosis in the brain tissue of MCAO rats. The tumor necrosis factor (TNF-α), IL-6, and malondialdehyde (MDA) levels decreased after NBP administration, while the activity of superoxide dismutase (SOD) and the ratio of GSH/GSSG in MACO rats increased. MACO caused non-heme iron accumulation in the brain tissue and Perl’s staining confirmed NBP attenuates ferroptosis in MACO rats. The protein expressions of SCL7A11 and glutathione peroxidase 4 (GPX4) decreased following MCAO, and NBP treatment subsequently increased the expression of SCL7A11 and GPX4. In vitro analysis in cortical neuron cells indicated that the GPX4 inhibitor reverses the inhibition of ferroptosis by NBP, which suggested that the SCL7A11/GPX4 pathway majorly contributed to the NBP ferroptosis protection effect.
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Translational Oncology
·
2024
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IF 4.5
Wei An,Kai Zhang,Guangbing Li,Shunzhen Zheng,Yukun Cao,Jun Liu
Cholangiocarcinoma remains a challenging primary hepatobiliary malignancy with dismal prognosis. Photodynamic therapy (PDT),a less invasive treatment, has been found to inhibit the proliferation and induce ferroptosis, apoptosis and necrosis in other tumor cells in recent years. Regrettably, the role and exact molecule mechanism of PDT is still incompletely clear in cholangiocarcinoma cells. Ferroptosis is a novel regulated cell death(RCD), which is controlled by glutathione peroxidase4(GPX4) with the characteristics of iron dependent and excessive intracellular accumulation of lipid peroxides. This novel form of RCD has attracted great attention as a potential new target in clinical oncology during recent years. In this study, we observed that hypericin mediated PDT(HY-PDT) could significantly inhibit the proliferation of the cholangiocarcinoma cells and suppress migration and the epithelial mesenchymal transition (EMT) as well. Then, we conducted transcriptome sequencing and bioinformatics analysis and observed that HY-PDT was most likely involved in ferroptosis, apoptosis, the EMT process and AKT/mTORC1 signaling pathways in cholangiocarcinoma cells. Next, a series of in vitro and in vivo experiments were performed to confirm that HY-PDT could trigger cholangiocarcinoma cells ferroptosis through inhibiting the expression of GPX4 protein. In terms of molecular mechanism, we found that HY-PDT induced ferroptosis by decreasing GPX4 expression via suppression of the AKT/mTORC1 signaling pathway. In addition, we also found that HY-PDT inhibit cholangiocarcinoma cells migration and the EMT process by inhibiting the AKT/mTORC1 pathway. Our study illustrated a new mechanism of action for HY-PDT and might throw light on the individualized precision therapy for cholangiocarcinoma patients.
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