MATERIALS & DESIGN
·
2025
·
IF 7.9
Li Ma,Sihong Guo,Xinlei Yang,Hongyu Gao,Jie Chen
The combination of apoptosis-ferroptosis-cuproptosis provides a beneficial method for enhancing the curative effect of ovarian cancer (OC). In this study, we design and synthesize a nano-drug delivery platform, HTC@DOX, which is achieved by the self-assembly of an amphipathic molecule HA-SS-TOS-DTPA, Cu 2+ , and doxorubicin (DOX). HTC@DOX bring the combination of chemotherapy (CT) from DOX and the chemodynamic therapy (CDT) from Cu 2+ . In vitro and in vivo experimental results show that HTC@DOX have excellent stability and glutathione responsiveness. This platform efficiently and purposely targets tumor sites, and destroy OC cells through the synergy of CT and CDT by induce apoptosis-ferroptosis-cuproptosis, thus enhancing the anti-cancer efficacy with a tumor reduction rate of 92.3 %. In addition, the results of electrocardiogram, ultrasound and histopathological staining demonstrate that HTC@DOX have superior biological safety and alleviate the cardiotoxicity caused by DOX alone. The results of bulk RNA sequencing and western blot show the alterations of apoptosis, ferroptosis, and cuproptosis related indicators, which further corroborates the anti-tumor efficacy of HTC@DOX. In brief, this study verifies the feasibility and effectiveness of the combination of CT and CDT in the treatment of OC by inducing apoptosis-ferroptosis-cuproptosis, offering an innovative approach for the treatment of cancer.
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Discover Oncology
·
2025
·Vol. 16
·期 1
·1-23
·
IF 2.9
Jiang Yingcun,Song Chao,Yan Jiyuan,Luo Liang,Gao Silong,Jiang Feng,Wei Zhangchao,Chen Jinwen,Liu Zongchao,Ge Jianhua
Ferroptosis has been demonstrated to have a significant role in osteosarcoma (OS), a highly aggressive and invasive malignant bone tumor. Nevertheless, the precise molecular mechanism underlying OS remains unknown. Understanding the makeup of the immune microenvironment in OS is crucial for its therapy, as the disease grows in the highly specialized, complex, and dynamic bone microenvironment. Resveratrol (Res) possesses anti-inflammatory, immunomodulatory, chemopreventive, antioxidant, and anticancer properties, it is unknown if it can modify ferroptosis to prevent OS. This time, using single-cell analysis and other bioinformatic studies, we will clarify the targets and composition of the immunological microenvironment of the ferroptosis process in OS, as well as the role of certain transcription factors in it. Ultimately, network pharmacology and vitro experiment have led to the initial identification of the molecular processes governing ferroptosis in OS, which are regulated by Res. The findings suggested the potential use of ALB, EGFR, GPX4, IL6, STAT3, and PTEN as OS prognostic and diagnostic biomarkers. Chondroblastic, myeloid cells, osteoblastic OS, CD4 + T, NK, CD8 + T, B cells, M1 macrophages, Chondro_Proli, etc. made up the majority of the immunological microenvironment of OS. The entire cellular trajectory demonstrates that immune cells infiltrating during the early stages of OS are mostly CD4 + T, NK, CD8 + T, B_cell, and M1 macrophages. This affects the development of myeloid cells and chondroblastic cells, which ultimately leads to the progression of highly malignant chondro cells to OS. Numerous pathways allow transcription factors including BCLAF1, MAF, SP1, TCF12, KLF11, and KMT2D to contribute to the development of tumors. Finally, by interacting with the aforementioned targets, cells, Res is thought to impede the evolution of OS. In conclusion, ferroptosis and alterations in the immunological milieu are significant factors in the development of OS, and Res may one day be employed as a therapeutic drug to treat OS.
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Zhiwei Huang,Xinze Li,Xuanhe Chen,Dedong Yu,Yingzheng Zhao
Ischemia-reperfusion (I/R)-induced acute kidney injury (AKI) triggers ferroptosis through oxidative stress and lipid peroxidation, exacerbating renal cell and tissue damage. 7-Dehydrocholesterol (7-D) was a pro-cholesterol molecule with a unique conjugated 5,7-diene structure that inhibits lipid peroxidation by trapping excessive radicals, thereby attenuating ferroptosis. However, direct administration of 7-D demonstrated limited efficacy in treating AKI. Here, we incorporated 7-D as the anti-ferroptotic agent and prepared it into liposomes (7-D@Lip) for the treatment of AKI. In addition, we added adenosine triphosphate (ATP) into the hydrophilic core of liposomes (7-D@A-Lip) to promote the uptake efficiency by damaged kidney cells. To enhance the distribution and accumulation of 7-D@A-Lip in the injured kidney, we extruded the renal cell membrane into the prepared liposomes (7-D@A-mLip). The results showed that 7-D@A-mLip could be rapidly internalized by hypoxia/reoxygenation-damaged renal cells, effectively inhibiting lipid peroxidation and alleviating ferroptosis-related injury. In addition, post-injection 7-D@A-mLip specifically accumulated in the renal tissues, reduced lipid hydroperoxide production by scavenging reactive oxygen species, and suppressed ferroptosis in the kidney, thereby preserving renal function in the AKI model. This study presented a promising renal-targeted delivery strategy for 7-D to mitigate ferroptosis in kidney disease.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-19
·
IF 12.6
Chen Yiting,Huang Xueli,Hu Ruining,Lu Enhao,Luo Kuankuan,Yan Xin,Zhang Zhiwen,Ma Yan,Zhang Minghe,Sha Xianyi
The limited efficacy and poor tumor accumulation remain crucial challenges for radiotherapy against lung cancer. To address these limitations, we rationally developed a polyunsaturated fatty acid (PUFA)-based nanoreactor (DHA-N@M) camouflaged with macrophage cell membrane to improve tumoral distribution and achieve peroxynitrite-augment ferroptosis for enhanced radiotherapy against lung cancer. After nebulization, the nanoreactors exhibited superior pulmonary accumulation in orthotopic lung cancer-bearing mice, with 70-fold higher than intravenously injected nanoreactors at 12 h post-administration, and distributed deeply in the tumors. DHA-N@M selectively released nitric oxide (NO) in glutathione (GSH)-enriched tumor cells, with consumption of GSH and subsequent inactivation of glutathione peroxidase 4 (GPX4). Under radiation, NO reacted with radiotherapy-induced reactive oxygen species (ROS) to generate peroxynitrite (ONOO-), resulting in redox homeostasis disruption. Combined with docosahexaenoic acid (DHA)-induced lipid metabolism disruption, overwhelming ferroptosis was induced both in vitro and in vivo. Notably, DHA-N@M mediated ferroptosis-radiotherapy significantly suppressed tumor growth with a 93.91% inhibition in orthotopic lung cancer models. Therefore, this design provides a nebulized ferroptosis-radiotherapy strategy for lung cancer.
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JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
·
2023
·Vol. 82
·期 2
·128-137
·
IF 3
Fu Caihua,Yu Shengbo,Liu Zhiquan,Wang Jiayu,Liu Ping,Su Guohai
Six-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 (PFKFB2) is a key regulator of glycolytic enzyme. This study identified whether PFKFB2 can regulate myocardial ferroptosis in ischemia/reperfusion (I/R) injury. Mice myocardial (I/R) injury and H9c2 cells oxygen-glucose deprivation/reperfusion
(OGD/R) models were established. PFKFB2 expression was enhanced in I/R mice and OGD/R H9c2 cells. Overexpression of PFKFB2 improves heart function in I/R mice. Overexpression of PFKFB2 inhibits I/R and OGD/R-induced ferroptosis in mice and H9c2 cells. Mechanistically, overexpression of PFKFB2
activates the adenosine monophosphate–activated protein kinase (AMPK). AMPK inhibitor compound C reverses effect of PFKFB2 overexpression in reducing ferroptosis under OGD/R treatment. In conclusion, PFKFB2 protects hearts against I/R-induced ferroptosis through activation of the AMPK
signaling pathway.
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MOLECULAR PHARMACEUTICS
·
2022
·
IF 5.364
Ying Chen,Xiaoming Liao,Pei Jing,Liangkui Hu,Zengqiu Yang,Yongchao Yao,Chunyan Liao,Shiyong Zhang
As the most common subtype in ovarian malignancies, high-grade serous ovarian cancer (HGSOC) made less therapeutic progress in past decades due to the lack of effective drug-able targets. Herein, an effective linoleic acid (LA) and glucosamine (GlcN) hybrid (LA–GlcN) was synthesized for the treatment of HGSOC. The GlcN was introduced to recognize the glucose transporter 1 (GLUT 1) overexpressed in tumor cells to enhance the uptake of LA–GlcN, and the unsaturated LA was employed to trigger ferroptosis by iron-dependent lipid peroxidation. Since the iron content of HGSOC was ∼5 and 2 times, respectively, higher than that of the normal ovarian cells and low-grade serous ovarian cancer cells, these excess irons make them a good target to enhance the ferroptosis of LA–GlcN. The in vitro study demonstrated that LA–GlcN could selectively kill HGSOC cells without affecting normal cells; the in vivo study revealed that LA–GlcN at the dose of 50 mg kg–1 achieved a comparable tumor inhibition as doxorubicin hydrochloride (4 mg kg–1) while the overall survival of mice was extended largely due to the low toxicity, and when the dose was increased to 100 mg kg–1, the therapeutic outcomes could be improved further. This dietary hybrid which targets the excess endogenous iron to activate ferroptosis represents a promising drug for HGSOC treatment.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
·
IF 7.129
Wenyu Miao,Lingling He,Yong Zhang,Xiaoyu Zhu,Yangming Jiang,Pengpeng Liu,Tao Zhang,Chunqi Li
Glucocorticoids (GCs) have been widely detected in the aquatic system. However, the hazardous effects of GCs on aquatic organisms were underestimated, and the mechanisms of GCs-induced toxic effects in fish were largely unknown. The zebrafish larvae at 3 dpf were exposed to dexamethasone (DEX) for 48 h, and the toxic effects and the underlying mechanisms were investigated in the current study. The T cells were ablated in zebrafish larvae after being treated with 1, 3, 10, 30 and 100 μM of DEX for 48 h. In addition, osteoporosis was induced and the regeneration of the caudal fin was inhibited, by 48 h-exposure to 10, 30 and 100 μM of DEX. The transcriptomic analysis, biochemical parameters and gene expression profiles revealed that ferroptosis possibly contributed to the DEX-induced toxic effects in zebrafish larvae. Finally, Fer-1 treatment partially attenuated the DEX-induced T cell ablation, but not osteoporosis in zebrafish larvae. Taken together, the current study proved the toxic effects of DEX on zebrafish larvae, and elucidated that ferroptosis was involved in DEX-induced toxicity, providing strong evidence for the toxic effects of GCs on aquatic organisms.
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EXPERIMENTAL CELL RESEARCH
·
2023
·
IF 3.7
Mingmei Li,Li Li,Xiaoxiao Cheng,Longyu Li,Kaijia Tu
Background Ovarian cancer has been a worldwide health burden for women and its progression is highly hypoxia-independent. Here, we investigated the exact mechanisms by which hypoxia contributes to the malignant progression of ovarian cancer. Method MTT, transwell, colony formation, and scratch wound healing assays were carried out for cellular functions. The underlying mechanism by which hypoxia functions was explored by RNA-seq, enrichment analysis, western blotting, qRT-PCR, flow cytometry, ChIP, luciferase reporter, and ELISA. Finally, animal experiments including the xenograft model and tumor metastasis model were constructed to validate the role of SLC2A12 in vivo . Results Hypoxia treatment promoted the cell proliferation, mobility, and colony growth abilities of the two ovarian cancer cell lines HO-8910 and A2780. RNA-seq and enrichment analysis showed that SLC2A12 was hyper-expressed under hypoxia condition and it may be related to glutathione and lipid metabolism. Besides, the expression of SLC2A12 was negatively correlated with overall survival. Hypoxia suppressed ferroptosis by SLC2A12 because silencing SLC2A12 declined the cell viability of HO-8910 and A2780 cells under hypoxia conditions, while the ferroptosis inhibitor ferrostatin-1 (Fer-1) breached that result and upregulated the expression of glutathione peroxidase 4 (GPX4). Moreover, hypoxia increased the expression of hypoxia inducible factor 1 A (HIF-1A), and the accumulated HIF-1A binds to hypoxia inducible factor 1 B (HIF1B) to form HIF-1 complex, then promoted the binding of hypoxic response elements (HRE) to SLC2A12 promoter by HIF-1/HRE signal. Subsequently, SLC2A12 regulated glutathione metabolism and in turn inhibited ferroptosis. The animal experiments indicated that silencing SLC2A12 could significantly inhibit tumor growth and metastasis in vivo . Conclusion Hypoxia promoted ovarian cancer progression by upregulating SLC2A12 and then regulating glutathione metabolism to inhibit ferroptosis.
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Redox Biology
·
2025
·
IF 11.9
Wa Li,Zihui Tang,Jiyang Xue
In head and neck squamous cell carcinoma, a "cold" (immune-desert) tumor microenvironment promotes immunosuppression, which is a critical driver of disease recurrence and therapeutic resistance. To address this challenge, we develop an innovative strategy to remodel the tumor immune microenvironment by disrupting intracellular redox balance to induce ferroptosis and immunogenic cell death, synergistically activating STING pathway to facilitating the transition of tumors from a “cold” to a “hot” immunophenotype. In this study, hyaluronic acid-functionalized hollow manganese dioxide nanoparticles loading β-lapachone (hMnL), engineered for targeted chemo-immunotherapy is constructed. In vitro investigations reveal that hMnL induces robust reactive oxygen species (ROS) generation, triggering ferroptosis and immunogenic cell death. Concurrently, Mn 2+ ions released from hMnL in response to the acidic tumor microenvironment activate the STING pathway, fostering dendritic cell (DC) maturation and M1 macrophage polarization. Activation of the ferroptosis and immune-related pathways was indicated by transcriptome sequencing, which identified significantly differentially expressed genes (e.g., Fth1 , Hmox1 , Calr ). In vivo , hMnL exhibits superior tumor-targeting efficacy and sustained intratumoral retention, culminating in potent tumor growth suppression. Furthermore, hMnL activates STING pathway in tumor, leading to enhanced CD8 + T cell infiltration, and a marked reduction in regulatory T cell (Treg) populations. Additionally, hMnL also shows good immunoprotective effects and long-term biosafety. These findings establish hMnL as a promising therapeutic platform that integrates targeted chemotherapy with immune modulation, offering a potent strategy to overcome immunosuppression and improve clinical outcomes in cancer.
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FOOD RESEARCH INTERNATIONAL
·
2025
·
IF 8
Yuhan Fu,Lirui Hou,Shirui Wang,Hongbo Hu,Shutao Yin
The accumulation of iron potentially results in organ damage and various diseases. Polyphenols can chelate iron in solution; however, there is a paucity of direct evidence supporting their efficacy in treating iron overload- mediated damage. This study sought to assess the chelating efficacy of galloyl glucoses with iron, as well as the potential of 1,2,3,4,6-Pentagalloyl glucose (PGG) to mitigate ferroptosis and liver injury induced by iron overload. RSL3 was employed to establish a cell model, while mice were treated with dextrose iron. PGG markedly mitigated cell death and the accumulation of lipid peroxides in RSL3 treated cells by chelating iron and inhibiting the RSL3-mediated autophagic degradation of ferroportin. Additionally, oral administration of PGG significantly reduced iron accumulation, inhibited oxidative stress, and ameliorated liver injury induced by iron overload. PGG has the potential to serve as an intervention for cell death and liver damage resulting from iron overload. The findings aim to contribute to the development of strategies for the intervention of iron overload-related injuries.
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Nano Today
·
2025
·
IF 10.9
Pengchen Wang,Jintong Na,Xiyu Liu,Minhui Cui,Ganghao Liang,Xinyue He,Haihua Xiao,Yongxiang Zhao,Yuan Liao,Liping Zhong
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, characterized by low immune response rates and high recurrence. This underscores an urgent need for more effective treatment strategies for liver cancer patients. Ferroptosis, a type of cell death associated with iron-dependent lipid peroxidation, has shown significant potential in HCC treatment. However, the efficacy of this monotherapy for tumor treatment remains limited. Enhancing reactive oxygen species (ROS) accumulation and lipid peroxide formation by inhibiting the tumor cell antioxidant system has emerged as a promising anti-tumor strategy. In this study, we developed a nanoplatform, NP (nanoparticle)-BSD@WFR, specifically tailored for HCC treatment. This system combines a biodegradable sonodynamic polymer (BSD) with warfarin (WFR), a VKORC1L1 inhibitor that prevents intracellular peroxide elimination and enhances ferroptosis. Under ultrasound irradiation, NP-BSD@WFR generates ROS and releases WFR, directly targeting cancer cells. Concurrently, ROS and WFR synergistically enhance lipid peroxide production in cancer cells, triggering ferroptosis and activating the immune system. Animal studies further demonstrate that combining sonodynamic therapy with WFR-induced ferroptosis produces a synergistic anti-tumor effect, promoting a strong immune response in vivo. This study introduces an innovative therapeutic approach combining sonodynamic therapy and WFR for HCC treatment and highlights its promising efficacy.
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ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Shiting Xu,Wenhao Gao,Shuang Lin,Bingkun Kang,Xiaoting Shi,Da Zheng,Longyun Xiao,Lingjun Zeng,Qian Zhang,Wenjun Tian,Hongtao Song
Ferroptosis, a newly recognized mode of regulated cell death characterized by iron-mediated accumulation of lipid peroxides, represents a viable treatment strategy for metastatic colorectal cancer (CRC). Nonetheless, the clinical effectiveness of single-agent ferroptosis inducers is constrained by the adaptive and self-repair capabilities of tumor cells. To address this limitation, this study proposes a self-amplifying ferroptosis nanodrug SOR/QUE@HSA, which is engineered by coencapsulating sorafenib (SOR) and quercetin (QUE) within human serum albumin (HSA). SOR/QUE@HSA offers a uniform structure, improved stability, and enhanced drug delivery efficiency. The released SOR and QUE impeded the uptake of glutamine (Gln) and cysteine (Cys) by targeting solute carrier family 7 member 11 (SLC7A11) and solute carrier family 1 member 5 (SLC1A5), respectively. This dual inhibition consequently disrupts the synthesis of glutathione (GSH), resulting in a marked downregulation of glutathione peroxidase 4 (GPX4), ultimately enhancing ferroptosis in CRC. Additionally, QUE inhibits hexokinase-II (HK-II), which results in decreased ATP production and lactate (LA) generation, thereby impeding tumor metastasis. In summary, our findings unveil a plausible role for the therapeutic potential of QUE as a ferroptosis-inducing anticancer agent, and the synergistic combination of QUE and SOR within this nanoplatform presents an option for treating metastatic CRC.
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