BIOCHEMICAL PHARMACOLOGY
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2026
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IF 6.5
Tong Sha,Kun Jiao,Jianing Li,Ye Zheng,Linbin Wang,Zhi Cui
Oral squamous cell carcinoma (OSCC) is an aggressive head and neck malignancy. Lysine acetyltransferase 2B (KAT2B) exerts tumor-suppressive functions in various cancers, yet its function in OSCC remains unclear. Through integrative analysis of five public transcriptomic datasets with validation in clinical tissues and cell lines, we identified a consistent reduction of KAT2B expression in OSCC. Functional assays demonstrated that KAT2B overexpression inhibited OSCC cell proliferation, tumorsphere formation, stemness marker expression, and in vivo tumor growth, whereas KAT2B silencing produced opposite effects. Furthermore, KAT2B overexpression enhanced RSL-3-induced ferroptosis, evidenced by increased Fe 2+ accumulation, elevated lipid reactive oxygen species (ROS) levels, aggravated mitochondrial damage, and reduced GPX4 protein; conversely, KAT2B knockdown conferred ferroptosis resistance. Mechanistically, integrating mRNA sequencing with the FerrDb database identified glutathione S-transferase zeta 1 (GSTZ1) (log 2 FC = 1.44, p < 0.001) as a key downstream target of KAT2B in ferroptosis regulation. ChIP-qPCR confirmed that KAT2B transcriptionally activates GSTZ1 by enhancing histone H3 lysine 9 acetylation (H3K9ac) enrichment at its promoter. Rescue assays further confirmed that depletion of GSTZ1 counteracted the effects of KAT2B overexpression on OSCC cell proliferation and ferroptosis. Collectively, we find that KAT2B transcriptionally activates GSTZ1 in a H3K9ac-dependent manner, which in turn inhibits GPX4 expression, thereby suppressing OSCC proliferation and stemness while enhancing ferroptosis sensitivity. This defines the KAT2B-GSTZ1 axis as a novel tumor-suppressive mechanism and an emerging therapeutic target for OSCC
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FREE RADICAL BIOLOGY AND MEDICINE
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2022
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IF 8.101
Shuhui Liu,Zhangshan Gao,Wanqiu He,Yuting Wu,Jiwen Liu,Shuo Zhang,Liping Yan,Shengyong Mao,Xizhi Shi,Wentao Fan,Suquan Song
Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disorders in the world, and yet has no approved pharmacotherapy due to the etiology is complex. In the last ten years, increasing evidence have identified the environmental pollutants as risk factors for MAFLD. However, the underlying mechanism remains unclear. Our study found that bromoacetic acid (BAA, a typical kind of environmental toxin) increased triglycerides and total cholesterol levels as well as induced obvious hepatic steatosis and inflammation. The lipidomics showed that ferroptosis was implicated in the environmental toxin–linked MAFLD. Besides, the analysis of microbial metabolomics showed significant change of gut microbiome in BAA groups and the content of gut microbiota metabolite (glycochenodeoxycholate, GCDCA) increased sharply. In vitro study, we observed features of ferroptotic cells by transmission electron microscopy after BAA/GCDCA treatment . Besides, we demonstrated that BAA/GCDCA significantly increased iron contents, with upregulating transferrin receptor (TFR) and acyl-CoA synthetase long-chain family 4 (ACSL4) expression levels. By contrast, iron chelator or silencing TFR relieved BAA/GCDCA-induced lipid metabolism disorder and inflammation. What's more, the interaction between TFR and ACSL4 was also identified. Taken together, we found that, in response to environmental toxin , gut microbiota metabolite GCDCA activates TFR-ACSL4-mediated ferroptosis, which triggered subsequent lipid metabolism disorder and inflammation. Moreover, these findings firstly highlighted the functional relevance among ferroptosis, lipid metabolism and gut microbiota metabolite during environmental pollutant exposure, which shed light on the deep mechanism of environmental toxin-related MAFLD, providing potential targets for the prevention of MAFLD.
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Nature Communications
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2022
·Vol. 13
·期 1
·1-13
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IF 17.694
Xiao Kui,Zhang Niyuan,Li Feifei,Hou Dayong,Zhai Xiaoyi,Xu Wanhai,Wang Gelin,Wang Hao,Zhao Liang
Medicinal applications of gold complexes have recently attracted attention due to their innovative antitumor mechanisms. In this work, two hypercoordinated carbon-centered gold clusters PAA4 and PAA5 are quantitatively synthesized by an intramolecular 6- exo - dig cyclization of polymetalated precursors. The on-bench and in vitro experimental studies demonstrate that the characteristic hypercarbon-tetragold(I) multi-center bonding in PAA4 and PAA5 not only guarantees their stability under common physiological conditions, but also facilitates a glutathione (GSH)-triggered prompt and synergetic release of active Au(I) ions in the GSH-overexpressed and acidic microenvironment of human bladder cancer EJ cells. The instantly massive release of coordination unsaturated Au(I) ions causes the efficient inhibition of thioredoxin reductases and then induces a rapid pro-oxidant response, consequently causing the occurrence of accelerated ferroptosis of EJ cells. As a result, these hypercarbon-centered gold(I) cluster prodrugs show high cytotoxicity to bladder cancer cell lines and thus exhibit a significant inhibition effect towards bladder tumors in vivo. Correlation of the synergetic domino dissociation of carbon-polymetal multi-center bonding in metal clusters with the accelerated ferroptosis of cancer cells provides a strategy for metallo-prodrugs and opens a broader prospect for the biological application of metal cluster compounds.
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FOOD AND CHEMICAL TOXICOLOGY
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2022
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IF 5.572
Hui Chen,Lixing Cao,Kai Han,Han Zhang,Jinling Cui,Xuan Ma,Shuang Zhao,Chong Zhao,Shutao Yin,Lihong Fan,Hongbo Hu
Patulin (PAT) is a common food-borne mycotoxin with diverse toxic effects including nephrotoxicity . The induction of oxidative stress is suggested to be a key mechanism contributed to toxicities of PAT. Reduced glutathione (GSH), a sulfhydryl-containing tripeptide , is a key reason for PAT-mediated oxidative stress. Cystine/glutamate antiporter (system x c − )-mediated cystine uptake plays a critical role in maintaining redox balance via promoting GSH biosynthesis. In this study, we addressed if GSH reduction by PAT was associated with inhibition of system x c − -mediated GSH biosynthesis. Results showed that PAT significantly decreased activity of SLC7A11, a core subunit of system x c − , through activating AMPK-mediated formation of beclin1-SLC7A11 complex. Furthermore, PAT promoted ferroptosis induced by a known ferroptosis inducer RSL3 in normal renal cells, and exacerbated folic acid-induced nephrotoxicity in a mouse model of acute kidney injury . The findings of the present study provide new insights into PAT-induced kidney toxicity, and implicate that patients with ferroptosis-associated diseases maybe more susceptible to PAT.
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FOOD AND CHEMICAL TOXICOLOGY
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2022
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IF 5.572
Dongxu Han,Yujie Yao,Lu Chen,Zhiying Miao,Shiwen Xu
Di(2-ethylhexyl) phthalate (DEHP) is a widely artificial persistent organic pollutant, the contamination of which infiltrates daily human life from many aspects, imperceptibly causing damage to multiple organs in the body, including the liver. Apigenin (APG) is widely distributed in vegetables and fruits and can relieve or prevent the injuries caused by exogenous chemicals through various pharmacological effects, such as antioxidant effects. To investigate the mechanism of DEHP-induced liver injury and the antagonistic effects of APG, we treated AML12 cells with 1 mM DEHP and/or APG. Ultrastructural morphology analysis indicated that DEHP induced typical ferroptosis-like damage. In addition, we found that DEHP exposure induced ferroptosis by enhancing reactive oxygen species (ROS) levels, disrupting iron homeostasis and lipid peroxidation, and regulating the expression of ferroptosis-related genes. Notably, supplementation with APG significantly inhibited these abnormal changes, and molecular docking further showed evidence of the activating effects of APG ligand on glutathione peroxidase 4 (GPX4). These results demonstrated that the protective effects of APG on DEHP-induced ferroptosis were achieved by activating GPX4 and suppressing intracellular iron accumulation. This information not only adds to DEHP toxicological data but also provides a basis for the practical application of APG.
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Acta Biomaterialia
·
2021
·
IF 8.947
Suleixin Yang,Ka Hong Wong,Peng Hua,Chengwei He,Hua Yu,Dan Shao,Zhi Shi,Meiwan Chen
Ferroptosis is a newly discovered non-apoptotic cell death form but its therapeutic efficacy triggered by traditional iron-based nanomaterials or classic drug inducers has been far from satisfactory due to the high glutathione (GSH) level in cancer cells and insufficient lipid peroxide production. Here we reported a ferroptosis/apoptosis combinational therapy by depleting GSH and downregulating GPX4 to disrupt redox homeostasis and amplify ferroptosis-related oxidation effect. In this study, we developed reactive oxygen species (ROS)-responsive serum-resistant nanoparticles with thioketal-crosslinked fluorinated polyethyleneimine 1.8K ( TK PF) as the core, which were wrapped with hyaluronic acid (HA) as the shell ( TK PFH NP) to co-deliver shGPX4 and shMTHFD2 plasmids for cancer treatment. The highly efficient and tumor-selective gene carrier TK PFH NPs revealed outstanding transfection efficiency (∼100 %) and sustained the efficiency (∼50 %) even in media containing 90 % FBS. Mediated by HA, TK PFH NPs actively targeted CD44 receptors, thus enabling efficient uptake by tumor cells and experiencing surface charge conversion to induce subsequent lysosomal escape. Then the TK PF NPs were effectively disintegrated by the abundant ROS in cancer cells, which facilitated the release of plasmids and avoided the cytotoxicity of cationic polymers. shGPX4 plasmid induced ferroptosis by producing ROS and lipid peroxides via downregulating GPX4, while shMTHFD2 triggered apoptosis by modulating NADPH/NADP and depleting GSH of the cancer cells. Moreover, GSH consumption caused by shMTHFD2 indirectly suppressed GPX4 and further augmented ferroptosis, showing synergistic anticancer effect against B16-F10 cells. Taken together, the rationally designed dual-gene loaded TK PFH NPs provided a safe and high-performance platform for enhanced ferroptosis-apoptosis combined anticancer efficacy based on gene therapy. Statement of significance The therapeutic efficacy of ferroptosis has been far from satisfactory due to high GSH level and insufficient lipid peroxide production in cancer cells. Herein, we reported a ferroptosis/apoptosis combinational therapy by depleting GSH and downregulating GPX4 to disrupt redox homeostasis and amplify ferroptosis-related oxidation effect. ROS-responsive serum-resistant nanoparticles were fabricated with thioketal-crosslinked fluorinated PEI 1.8K ( TK PF) as the core and hyaluronic acid (HA) as the shell ( TK PFH NP) to co-deliver shGPX4 and shMTHFD2 plasmids. The shGPX4 plasmid induced ferroptosis by producing ROS and lipid peroxides via downregulating GPX4, while shMTHFD2 triggered apoptosis by modulating NADPH/NADP and depleting GSH. The rationally designed dual-gene loaded TK PFH NPs provided a safe and high-performance platform aimed for enhanced ferroptosis-apoptosis combined anticancer efficacy.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
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IF 5.8
Yue Hu,Qing Nie,Xianling Cong,Wen Wu,Qiong Wu,Qihui Liu,Yuanyuan Li,Haiyan Liu,Jingyan Ge,Fangfang Chen
Cancer represents a significant global public health challenge, and conventional cancer therapies such as surgery and chemoradiotherapy are not enough due to the increased complexity of cancer. Nanotechnology has the potential to revolutionize tumor treatments by integrating gene therapy, tumor targeting, and drug delivery. In this study, we demonstrated that Snail2 plays a crucial role in the migration and invasion of lung and liver carcinoma. We proposed a novel approach to synergize the aminated crosslinking dextran coat of superparamagnetic iron oxide nano worms (CLIO-NH 2 , CN) with small interfering Snail2 RNA (siSnail2). The efficiency of siSnail2 delivery was significantly improved by coating CN with N-Isopropylacrylamide-modified polyethylenimine (CNP). In vitro, experiments revealed that CNP@siSnail2 effectively inhibited cancer cell EMT, migration, and invasion. Moreover, CNP@ siSnail2 promoted cancer cell death through various mechanisms, including apoptosis and ferroptosis . The combination of CNP@ siSnail2 and cisplatin significantly improved the anti-tumor effect of the treatment. Animal models demonstrated that the combined treatment of CNP@ siSnail2 and cisplatin resulted in excellent tumor inhibition effects. Our findings provide a potential combined treatment strategy for cancer therapy.
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ADVANCED FUNCTIONAL MATERIALS
·
2023
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IF 19
Yanqiu Wang,Lu Tan,Wanqian Zhang,Yi Yang,Changqing Li,Hongli Li,Kaiyong Cai,Yan Hu,Zhong Luo,Minghan Liu
Intervertebral disc degeneration (IDD) remains an essential challenge in the clinics due to the ferroptosis of nucleus pulposus cells (NPCs) and the imbalance of extracellular matrix (ECM) metabolism. Here, a dynamic hydrogel (HPGO) based on oxidized hyaluronic acid (OHA) and polyvinyl alcohol (PVA) for the integration of oridonin (Ori)-loaded NPC membrane-based nanovesicles is proposed, which is further grafted with growth and differentiation factor 5 (GDF5) on the OHA chain via Schiff base ligation. The precursors can rapidly form mechanically resilience hydrogels after injection into nucleus pulposus (NP) through the formation of various dynamic bonds. Meanwhile, the acidic pH in the degenerated NP can trigger the responsive release of GDF5, which may cooperate with Ori to alleviate inflammation in the microenvironment for restoring the metabolic homeostasis of ECM. In addition, the Schiff base moieties in HPGO hydrogel can scavenge free ferrous ions in the microenvironment to strengthen the dynamic bonds for self-regulated reinforcement, thus providing mechanical support for the degenerated intervertebral discs (IVDs). Furthermore, HPGO hydrogel can enhance ferroptosis resistance of NPCs by activating the nuclear factor erythoid 2-related factor 2 signaling pathway. Overall, HPGO hydrogel can mechanically support the damaged IVDs as well as reversing their degenerative status through cooperative ferroptosis inhibition, which provides an approach for the clinical treatment of IDD.
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ANALYTICAL CHEMISTRY
·
2023
·
IF 7.4
Dan Sun,Guohua Qi,Xuan Yi,Hongyan Zhu,Yongdong Jin
Studying the oxidative stress, especially the reactive oxygen species (ROS) response of ferroptosis, is crucial for the diagnosis and treatment of cancer based on ferroptosis. However, reliable quantitative analysis of intracellular ROS in cancer treatment for drug screening is still a challenge. Herein, a superior ratiometric SERS nanoprobe was developed for in situ, real-time, and highly sensitive detection of content variation of H2O2 within living cells. The SERS nanoprobe was prepared by coassembly of the internal standard molecule p-mercaptobenzonitrile and the reporter molecule p-mercaptophenylboronic acid on the surface of gold nanoparticles, used for synergistic calibration and detection of H2O2, which enables reliable detection of the true content of intracellular H2O2 without the interference of other substances in cells. Based on the nanoprobe, we found that the level of intracellular H2O2 of cancer cells was increased after the nicotinamide adenine dinucleotide (NADH) treatment, with a dose-dependence to the concentration of NADH. High doses of NADH (above 20 mM) can induce cell death by means of ferroptosis associated with the level elevation of intracellular lipid hydroperoxides. This study highlights the potential of the SERS nanoprobe for tracking content variation of cellular H2O2 and understanding its roles in screening new anticancer drugs.
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JOURNAL OF MEDICINAL CHEMISTRY
·
2022
·
IF 8.039
Haohao Wang,Di Wu,Chunyu Gao,Hongbo Teng,Yan Zhao,Zhongmei He,Weijia Chen,Ying Zong,Rui Du
In this study, 70 new seco-lupane triterpene derivatives were designed, synthesized, and characterized, and their in vitro anticancer activities were evaluated. Structure–activity relationship studies showed that most compounds inhibited the growth of a variety of tumor cells in vitro. With the extension of alkyl chains, the activity of azole compounds gradually increased while that of indole compounds first increased and then decreased. Moreover, all indole derivatives showed stronger anticancer activity than azole derivatives. In addition, compound 21 showed the strongest inhibitory effect on HepG2 cells with an IC50 value of 0.97 μM. Mechanistic studies showed that compound 21 coregulates the cell death process by inducing ferroptosis and regulating the cell cycle. In conclusion, compound 21 can be used as a ferroptosis inducer and cycle blocker to regulate the HepG2 death process, and it has the potential to become an effective new drug for the treatment of hepatocellular carcinoma.
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Biomaterials Research
·
2023
·Vol. 27
·期 1
·1-20
·
IF 11.3
Jiang Hao,Tian Hailong,Wang Zhihan,Li Bowen,Chen Rui,Luo Kangjia,Lu Shuaijun,Nice Edouard C.,Zhang Wei,Huang Canhua,Zhou Yuping,Zheng Shaojiang,Gao Feng
Background Colorectal cancer (CRC) is the second most deadly cancer worldwide, with chemo-resistance remaining a major obstacle in CRC treatment. Notably, the imbalance of redox homeostasis-mediated ferroptosis and the modulation of hypoxic tumor microenvironment are regarded as new entry points for overcoming the chemo-resistance of CRC.
Methods Inspired by this, we rationally designed a light-activatable oxygen self-supplying chemo-photothermal nanoplatform by co-assembling cisplatin (CDDP) and linoleic acid (LA)-tailored IR820 via enhanced ferroptosis against colorectal cancer chemo-resistance. In this nanoplatform, CDDP can produce hydrogen peroxide in CRC cells through a series of enzymatic reactions and subsequently release oxygen under laser-triggered photothermal to alleviate hypoxia. Additionally, the introduced LA can add exogenous unsaturated fatty acids into CRC cells, triggering ferroptosis via oxidative stress-related peroxidized lipid accumulation. Meanwhile, photothermal can efficiently boost the rate of enzymatic response and local blood flow, hence increasing the oxygen supply and oxidizing LA for enhanced ferroptosis.
Results This nanoplatform exhibited excellent anti-tumor efficacy in chemo-resistant cell lines and showed potent inhibitory capability in nude mice xenograft models.Conclusion sTaken together, this nanoplatform provides a promising paradigm via enhanced ferroptosis and alleviated hypoxia tumor microenvironment against CRC chemo-resistance.Graphical Abstract
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BIOMACROMOLECULES
·
2021
·
IF 6.988
Jing Li,Junhua Li,Yuji Pu,Sai Li,Wenxia Gao,Bin He
In this study, we reported a nanocomplex (PAF) of PEGylated polygalacturonic acid, 5,10,15,20-tetrakis (4-aminophenyl) porphyrin (TAPP), and Fe3+ for photodynamic therapy (PDT)-enhanced ferroptosis in cancer treatment. PAF exhibited a size of 135 nm and a TAPP and Fe3+ loading content of 6.99 and 0.77%, respectively. The singlet oxygen (1O2) generation capacity of TAPP can be activated and significantly enhanced at acidic pH (4.5–5.0). Besides, the enhanced near-infrared absorption of TAPP at acidic pH enabled a further increase in 1O2 generation capability by a near-infrared laser (760 nm). The polysaccharide-based polymer carrier offers excellent biocompatibility, and PAF displayed a proliferative effect in both normal (L929) and cancer (B16) cells. However, upon light irradiation, PAF exhibited high toxicity to B16 melanoma cells by intracellular reactive oxygen species elevation, glutathione depletion, and lipid peroxidation. PAF displayed a much better anticancer effect than the nanocomplex containing Fe3+ or TAPP alone, indicating the PDT-enhanced ferroptosis in PAF. This study suggested that PDT-enhanced ferroptosis could be a facile and robust strategy of nanotherapeutics with high potency, tumor selectivity, and excellent biocompatibility.
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