CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Ning Zhang,Zijia Wang,Gen Li,Mingzhe Zhang,Quan Liu,Chunxiu Cai,Yanfei Shang,Hailiang Zhu,Hailong An,Shenzhen Ren
The development of multidrug resistance (MDR) is the primary contributor to the failure of cancer treatment, ultimately leading to tumor recurrence and metastasis. Ferroptosis, an iron-dependent cell death form related to the accumulation of lipid peroxidation (LPO), has the potential to circumvent MDR. Furthermore, recent breakthroughs have confirmed that the inhibition of cyclooxygenase-2 (COX-2) not only facilitate LPO and ferroptosis, but also suppress the expression of p-glycoprotein. Therefore, the combination of immunogenic ferroptosis with COX-2 inhibitors may be an enticing approach for overcoming tumor resistance and metastasis. Herein, polyphenolic COX-2 inhibitors are first screened using molecular docking, enzyme-linked immunosorbent assay, and combination index analysis. Then, a carrier-free metal-phenolic networks are constructed based on the coordination between polyphenolic COX-2 inhibitors and Fe 3+ , and DOX and dopamine-modified hyaluronic acid are directly decorated using a one-pot process. The nanosystem can selectively inhibit the COX-2 pathway, thereby suppressing the expression of p-glycoprotein and enhancing Fe 3+ -induced ferroptosis; Additionally, the nanosystem demonstrates excellent photothermal performance, promoting ferroptosis and synergistically triggering strong immune responses against tumor metastasis. The RNA-seq analysis further confirmes the transcriptomic alterations in drug resistance and ferroptosis pathways induced by the nanosystem. Taken together, this study provides a promising strategy for efficient cancer treatment.
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BIOMATERIALS
·
2024
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IF 12.8
Pingting Ye,Chunhui Wang,Yixuan Wen,Kang Fang,Qi Li,Xin Zhang,Jingxian Yang,Ruihao Li,Mengyao Chen,Xiaohan Tong,Shuo Shi,Chunyan Dong
Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer due to poor immunogenicity and limited immune cell infiltration, efficient therapeutics are still deficiency. Ferroptosis, a reactive oxygen species (ROS)-reliant cell death, can enhance cellular immunogenicity and then active immune system. To sustain a long-term “hot” tumour immune microenvironment (TIME), an immune-modulator is indispensable. Metformin (MET), a commonly used oral drug for type 2 diabetes, has played a vital role in fostering an immunostimulatory environment. Herein, we confirm the TIME can be remodeled by MET and further promotes ferroptosis via upregulating cellular concentration of l -Glutamine. In light of this, we have design a self-assembled MET-loaded Fe 3+ -doped polydopamine nanoparticle (Fe-PDA-MET NP) that can disorder the cellular redox homeostasis and induce robust ferroptosis under 808 nm irradiation, resulting in a strong immune response. Based on the function of MET, there is a marked increase in the infiltration of activated CD8 + T cells and NK cells, which subsequently augments ferroptosis to a greater extent. Taken together, Fe-PDA-MET NPs activate a ferroptotic positive-feedback loop for effectively control TNBC progression, which offers a promising therapeutic modality to enhance the immunogenicity and reshape the TIME.
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International Journal of Nanomedicine
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2024
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IF 6.6
Siyan Pang,Chenchen Geng,Zihan Fan,Min Hou,Huilan Mao,Shuang Tao,Jing Wang,Yulun Wu,Ke Wei,Yunhao Li,Liuyang Yan,Qingling Yang,Changjie Chen,Wenrui Wang
Background Breast cancer is the most common cancer in women and one of the leading causes of cancer death worldwide. Ferroptosis, a promising mechanism of killing cancer cells, has become a research hotspot in cancer therapy. Simvastatin (SIM), as a potential new anti-breast cancer drug, has been shown to cause ferroptosis of cancer cells and inhibit breast cancer metastasis and recurrence. The purpose of this study is to develop a novel strategy boosting ferroptotic cascade for synergistic cancer therapy.Methods In this paper, iron base form of layered double hydroxide supported simvastatin (LDHs-SIM) was synthesized by hydrothermal co-precipitation method. The characterization of LDHs-SIM were assessed by various analytical techniques, including ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). Biological activity, ferroptosis mechanism and biocompatibility were analyzed through in vivo and in vitro analysis, so as to evaluate its therapeutic effect on breast cancer.Results The constructed LDHs-SIM nanosystem can not only release SIM through mevalonate (MVA) pathway, inhibit the expression of glutathione peroxidase 4 (GPX4), inhibit the expression of SLC7A11 and reduce the synthesis efficiency of GSH, but also promote the accumulation of Fe2+ in cells through the release of Fe3+, and increase the intracellular ROS content. In addition, LDHs-SIM nanosystem can induce apoptosis of breast cancer cells to a certain extent, and achieve the synergistic effect of apoptosis and ferroptosis.Conclusion In the present study, we demonstrated that nanoparticles of layered double hydroxides (LDHs) loaded with simvastatin were more effective than a free drug at inhibiting breast cancer cell growth, In addition, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that LDHs-SIM could serve as a safe and high-performance platform for ferroptosis−apoptosis combined anticancer therapy.
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BIOMATERIALS
·
2024
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IF 12.8
Jingjing Shen,Kai Feng,Jing Yu,Yaxuan Zhao,Ruifang Chen,Hehua Xiong,Yiling Ruan,Zhengtao Xu,Tao Zhang,Xiaolian Sun
Ferroptosis is an iron-dependent form of programmed cell death with the potential to reverse traditional cancer therapy resistance. The combination of ferroptosis with chemotherapy, photodynamic therapy and X-ray therapy has demonstrated remarkably improved therapeutic efficiency. Radiopharmaceutical therapy (RPT) is an emerging approach that achieves precise radiation to diseased tissues via radionuclide delivery. However, insufficient accumulation and retention of therapeutic radiopharmaceuticals in tumor region as well as cancer radioresistance impact treatment efficacy. Here, a nanoassembly of renal clearable ultrasmall iron nanoparticles (USINPs) and 131 I-aPD-L1 is prepared via the affinity of fluorophenylboronic acid modified on the USINPs with 131 I-aPD-L1. The 150 nm USINAs( 131 I-aPD-L1) nanoassembly is stable in blood circulation, effectively targets to the tumor and disassembles in the presence of ATP in the tumor microenvironment. Both in vitro and in vivo experiments prove that USINPs-induced ferroptosis boosted the tumor radiosensitization to 131 I while 131 I-mediated RPT further enhanced ferroptosis. Meanwhile, the immunogenic cell death caused by RPT and ferroptosis combined with PD-L1 immune checkpoint blockade therapy exhibits a strong antitumor immunity. This study provides a novel way to improve the tumor accumulation of ferroptosis inducer and radiopharmaceuticals, insights into the interaction between RPT and ferroptosis and an effective SPECT-guided ferroptosis-enhanced radio-immunotherapy.
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高影响因子
BIOMATERIALS
·
2025
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IF 12.9
Yan Gao,Zilin Song,Wenxin Gan,Xue Zou,Yaning Bai,Xiuli Zhao,Dawei Chen,Mingxi Qiao
Despite the promise of ferroptosis in cancer therapy, selectively inducing robust ferroptosis in cancer cells remains a significant challenge. In this study, manipulation of fatty acids β-oxidation (FAO) by combination of mild photodynamic therapy (PDT) and inhibition of triglycerides (TGs) synthesis was found to induce robust and iron-independent ferroptosis in cancer cells with dysregulated lipid metabolism for the first time. To achieve that, TGs synthesis inhibitor of xanthohumol (Xan) and FAO initiator of tetrakis (4-carboxyphenyl) porphyrin (TCPP) were co-delivered by a nanoplexes composed of pH-responsive amphiphilic lipopeptide C 18 -pHis 10 and DSPE-PEG 2000 . TCPP was found to rapidly increase the intracellular ROS under laser irradiation without inducing antioxidant response and apoptosis, activating the AMPK in cancer cells and accelerating mitochondrial FAO. Xan fueled the mitochondrial FAO with substrates by suppressing the conversion of fatty acids (FAs) to TGs. This also led to augmented intracellular polyunsaturated fatty acids (PUFAs) and PUFAs-phospholipids levels, increasing the intrinsic susceptibility of cancer cells to lipid peroxidization. As a result, the excessive ROS generated from the sustained mitochondrial FAO caused remarkably lipid peroxidation and ultimately ferroptosis. Collectively, our study provides a new approach to selectively induce iron-independent ferroptosis in cancer cells by taking advantage of dysregulated lipid metabolism.
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BIOLOGICAL & PHARMACEUTICAL BULLETIN
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2025
·Vol. 48
·期 7
·1096-1106
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IF 1.7
Tao Feng,Guofang Hu,Yinjun Luo,Xin Zhang,Hong Chen,Zuoren Liang,Xianjiao He,Shijing Ma,Jinting Wei,Xiaoyan Fang,Biao Li,Jinhua Wang,Suchan Liao
Nasopharyngeal carcinoma (NPC) is a highly invasive form of head and neck cancer that arises from nasopharyngeal epithelial cells. Celastrol and curcumin, both derived from traditional Chinese medicine, have demonstrated antitumor potential. However, the clinical application of these compounds is limited by their low bioavailability and/or toxicity. Cancer cell viability, apoptosis, autophagy, ferroptosis, and mitochondrial fission- and fusion-related proteins were evaluated following treatment with celastrol alone, curcumin alone, and their combination. The results indicated that low doses of celastrol (0.7 μM) alone do not inhibit proliferation in NPC cells. However, when combined with curcumin, there is a significant enhancement of the antiproliferative effect. There was no significant alteration in the expression levels of the apoptosis-related proteins BCL2-associated X and cleaved caspase 3 in either the curcumin alone or the combined treatment groups compared to the control group. Interestingly, the combined treatment significantly increased the ferroptosis contributor acyl-CoA synthetase long-chain family member 4 while notably decreasing solute carrier family 7 member 11 and glutathione peroxidase 4, accompanied by increased phosphorylation of dynamin-related protein 1. Furthermore, the combined treatment exhibited significant antitumor efficacy with low toxic side effects in a xenograft model. In conclusion, our study provides new insights into combination therapies to enhance anti-NPC efficacy.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Huanqi Zhang,Xiaozhe Chen,Fuqing Liu,Yanju Bi,Meichen Gao,Xiaojing Li
Long-term environmental exposure to chlorpyrifos (CPF) can cause intestinal damage. Baicalein (BAI) helps aquatic organisms resist environmental pollution stress. Adenosine 5′-monophosphate activated protein kinase (AMPK) is a key molecule in energy regulation; however, the mechanism by which BAI inhibits CPF-induced autophagy/ferroptosis remains unclear. Based on reported environmental concentrations and IC 50 values of CPF, we established models using the midgut of carp and Epithelioma papulosum cyprini (EPC) cells exposed to CPF with or without BAI treatment. Transcriptomics and network pharmacology were used to analyze the key pathways affected by CPF and BAI. Tissue damage, cell cycle regulation, autophagy, ferroptosis, and mitochondrial function were assessed. The effect of BAI on AMPK–unc-51-like autophagy-activating kinase 1 (ULK1) binding was confirmed by molecular dynamics simulation, co-immunoprecipitation, and laser confocal analysis. In addition, the regulatory impact of an AMPK activator on the autophagy/ferroptosis axis was examined. Results indicated that BAI alleviated CPF-induced pathological changes and mitochondrial damage. CPF exposure caused tight junction disruption, mitochondrial depolarization, and reactive oxygen species and mitochondrial reactive oxygen species production. Transcriptomic analysis revealed that CPF toxicity is related to phagosomes, cell cycle regulation, and ferroptosis. By targeting AMPK, BAI prevents the formation of the AMPK–ULK1 complex and inhibits the CPF-induced cascade involving excessive autophagy, cell cycle arrest, and ferroptosis. In conclusion, BAI targets AMPK to prevent binding with ULK1, thereby suppressing the CPF-activated autophagy/ferroptosis axis, reversing mitochondrial dysfunction, and restoring intestinal homeostasis.
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MOLECULAR PHARMACEUTICS
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2025
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IF 4.5
Ying Yin,Xiang Cheng,Duoyang Fan,Yanpeng Fang,Haohan Li,Xingru Zhou,Hongqi Guo,Wenbin Zeng,Fei Chen
Photodynamic therapy (PDT), a noninvasive and spatiotemporally controlled cancer treatment, often suffers from the mitochondrial or lysosomal accumulation of conventional photosensitizers (PSs), primarily triggering apoptosis and limiting efficacy against apoptosis-resistant tumors. Targeting the plasma membrane offers a promising, yet less explored, strategy to induce immunogenic cell death pathways like ferroptosis and pyroptosis, which can overcome therapeutic resistance. However, PSs capable of simultaneously targeting the plasma membrane and activating both ferroptosis and pyroptosis are scarce. Here, we present a simple and rational π-bridge engineering strategy to develop multifunctional membrane-anchored PSs. Among our synthesized compounds, TDTP exhibits strong near-infrared (NIR) fluorescence, distinct aggregation-induced emission (AIE) characteristics, superior reactive oxygen species (ROS) generation, and precise plasma membrane localization. Upon light activation, TDTP induces synergistic ferroptotic-pyroptotic cell death, leading to highly efficient tumor ablation at nanomolar concentrations (IC50 = 26.07 nM). In vivo studies demonstrate that TDTP enables high-contrast NIR imaging and substantially inhibits tumor growth under image-guided PDT. This work highlights a facile yet powerful strategy for constructing membrane-specific PSs and introduces a rare class of theranostic agents capable of inducing dual cell death pathways.
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ACS Applied Materials & Interfaces
·
2025
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IF 8.2
Zejun Lin,Junhong Ling,A. M. Omer,Xiao−kun Ouyang,Lin Mei,Nan Wang
Combining photothermal therapy (PTT) with chemotherapy shows promise for cancer treatment, but its efficacy is limited by heat shock protein (HSP)-induced thermoresistance and P-glycoprotein (P-gp)-mediated drug efflux. To overcome these challenges, we developed a tumor microenvironment-responsive microneedle platform for synergistic chemotherapy, PTT, and ferroptosis in breast cancer. The system employs Fe3+-coordinated dihydromyricetin (DMY) nanocarriers encapsulating doxorubicin (DMFD NPs) integrated into a flexible polyvinylpyrrolidone (PVP) microneedle patch. The patch adheres tightly to tumors, enabling the rapid delivery and targeted release of DMFD NPs under laser irradiation and acidic conditions. Released Fe3+/Fe2+ ions generate reactive oxygen species (ROS) via Fenton reactions, synergizing with PTT to induce ferroptosis. DMY concurrently inhibits HSP and P-gp, enhancing photothermal-chemotherapy efficacy. In vivo, this approach achieved 92% tumor inhibition, demonstrating its potential to address the limitations of conventional PTT and chemotherapy through localized multifunctional action.
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DYES AND PIGMENTS
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2025
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IF 4.2
Guo-Ping Zu,Pingping Xiong,Meng-Chen Pei,Chengjie Wang,Huawei Niu,Hong Chen,Yong Meng
Peroxynitrite (ONOO − ) is closely associated with several pathophysiological events due to its high oxidation and nitrification reactivity, which can cause irreparable damage to a variety of biomolecules when present in excess. Consequently, the development of a reliable ONOO − detection method is essential for understanding its role. Given the significant imaging advantages of ratiometric and near-infrared (NIR) probes, a ratiometric NIR fluorescence probe ( FYS ) was developed for the visual detection of ONOO − both in vitro and in vivo . Probe FYS offers several benefits, including a large fluorescence emission shift (184 nm), a low detection limit (0.75 μM), good selectivity, and rapid detection. Inspired by these outstanding characteristics, it has been successfully utilized for imaging endogenous and exogenous ONOO − in cells. More importantly, this probe could be used to monitor variations in ONOO − levels as ferroptosis progresses. We anticipate that this probe will be widely applied as a potent tool to investigate the biological function of ONOO − , thereby facilitating a deeper understanding of ferroptosis.
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Nano Today
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2025
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IF 10.9
Jiarui Wang,Gao He,Lile Dong,Xujian Yang,Hongpeng You,Shuyan Song
Poor separation and rapid recombination of electron-hole pairs hinder the reactive oxygen species (ROS) generation efficiency of sonosensitizers and hampers the efficacy of tumor therapy. To overcome these obstacles, the nanoconfinement-enhanced strategy was proposed to construct polyvinylpyrrolidone-modified ZnO 2 nanomedicines loaded with IrO 2 (IZH) for piezoelectric therapy. Nanoconfinement activates IrO 2 nanoclusters for carrier separation, and the ultrasound current density of IZH (29.4 nA cm −2 ) is 2.9 times that of ZnO 2 (10.3 nA cm −2 ) under the ultrasound irradiation. In addition, the internal electric field between IrO 2 and ZnO 2 accelerates electron directed migration under ultrasound. Interestingly, this strategy augmented ROS generation induces ferroptosis-like/apoptosis with the tumor inhibition rate of 90 %. This study provides an promising nanoplatform to trigger efficient carrier separation for enhancing ROS generation through an iridium-based nanoconfinement piezoelectric sonosensitizer on ferroptosis-like and apoptosis, providing new guidance for exploring candidates for piezoelectric therapy.
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BIOCHEMICAL PHARMACOLOGY
·
2025
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IF 5.6
Jiajian Wang,Lanqing Zhang,Runfang Li,Rui Yang,Fan Yang,Fei Yu,Jihong Zhang
TP53, the most frequently mutated gene in human cancers, undergoes a functional transformation from a tumor suppressor to an oncoprotein, thereby enhancing tumor aggressiveness, metastatic potential, and resistance to therapy. Given the prevalence of p53 mutations in cancer, the reactivation of wild-type p53 function presents a compelling therapeutic strategy for these malignancies. In this study, we identified gambogic acid (GA), a natural compound, as a potent reactivator of mutant p53 transcriptional activity. Immunofluorescence and co-immunoprecipitation assays revealed that GA treatment upregulates wild-type p53 expression while depleting mutant p53 in cancer cells. The time-dependent restoration of p53′s DNA-binding capacity and transcriptional regulatory activity by GA was further demonstrated through EMSA and ChIP. Consequently, GA robustly induced the expression levels of canonical p53 downstream target genes, confirming functional restoration of p53 signaling. 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.
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