SCIENCE OF THE TOTAL ENVIRONMENT
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2024
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IF 8.2
Yu Zhu,Xiang-Yu Ma,Ling-Ge Cui,Ya-Ru Xu,Chen-Xi Li,Milton Talukder,Xue-Nan Li,Jin-Long Li
Di(2-ethylhexyl) phthalate (DEHP) is a synthetic chemical applied as a plasticizer. As an environmental toxicant, DEHP poses a serious health threat. Many studies have revealed that DEHP can cause lead to various degrees of damage to the kidney. However, the evidence of DEHP-induced renal ferroptosis has not been reported. The purpose of this work was to probe the specific role of lipophagy in DEHP-induced renal injury and to investigate the relationship between lipophagy and ferroptosis. Quail were treated with DEHP (250 mg/kg BW/day, 500 mg/kg BW/day and 750 mg/kg BW/day) for 45 days. Microstructural and ultrastructural observations showed that DEHP caused damage to glomerular and tubular cells, and autophagy with multilayer structures were observed, suggesting that DEHP can induce lipophagy. The results indicated that the iron homeostasis was abnormal and the lipid peroxidation was increased. SLC7A11 and SLC3A2 were down-regulated. PTGS2, ACSL4 and LPCAT3 were elevated. In conclusion, DEHP could induce lipid peroxidation, lead to ferroptosis, and damage renal cells. Therefore, the relationship between lipophagy and ferroptosis was elucidated, which provided a new basis for intervention and prevention of DEHP increased diseases.
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TOXICOLOGY
·
2024
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IF 4.8
Jianan Zhai,Zhengguo Chen,Qi zhu,Zhifang Guo,Xiance Sun,Liping Jiang,Jing Li,Ningning Wang,Xiaofeng Yao,Cong Zhang,Haoyuan Deng,Shaopeng Wang,Guang Yang
Patulin (PAT), the most common mycotoxin, is widespread in foods and beverages which poses a serious food safety issue to human health. Our previous research confirmed that exposure to PAT can lead to acute kidney injury (AKI). Curcumin is the most abundant active ingredient in turmeric rhizome with various biological activities. The aim of this study is to investigate whether curcumin can prevent the renal injury caused by PAT, and to explore potential mechanisms. In vivo , supplementation with curcumin attenuated PAT-induced ferroptosis. Mechanically, curcumin inhibited autophagy, led to the accumulation of p62 and its interaction with Keap1, promoted the nuclear translocation of nuclear factor E2 related factor 2 (Nrf2), and increased the expression of antioxidant stress factors in the process of ferroptosis. These results have also been confirmed in HKC cell experiments. Furthermore, knockdown of Nrf2 in HKC cells abrogated the protective effect of curcumin on ferroptosis. In conclusion, we confirmed that curcumin mitigated PAT-induced AKI by inhibiting ferroptosis via activation of the p62/Keap1/Nrf2 pathway. This study provides new potential targets and ideas for the prevention and treatment of PAT.
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Small
·
2024
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IF 13
Shiyan Fu,Yong Li,Li Shen,Yonglai Chen,Jingxuan Lu,Yonghong Ran,Yazhen Zhao,Hong Tang,Longfei Tan,Qinyang Lin,Yuhui Hao
Unavoidable damage to normal tissues and tumor microenvironment (TME) resistance make it challenging to eradicate breast carcinoma through radiotherapy. Therefore, it is urgent to develop radiotherapy sensitizers that can effectively reduce radiation doses and reverse the suppressive TME. Here, a novel biomimetic PEGylated Cu 2 WS 4 nanozyme (CWP) with multiple enzymatic activities is synthesized by the sacrificing template method to have physical radiosensitization and biocatalyzer-responsive effects on the TME. Experiment results show that CWP can improve the damage efficiency of radiotherapy on breast cancer cell 4T1 through its large X-ray attenuation coefficient of tungsten and nucleus-penetrating capacity. CWP also exhibit strong Fenton-like reactions that produced abundant ROS and GSH oxidase-like activity decreasing GSH. This destruction of redox balance further promotes the effectiveness of radiotherapy. Transcriptome sequencing reveals that CWP induced ferroptosis by regulating the KEAP1/NRF2/HMOX1/GPX4 molecules. Therefore, owing to its multiple enzymatic activities, high-atomic W elements, nucleus-penetrating, and ferroptosis-inducing capacities, CWP effectively improves the efficiency of radiotherapy for breast carcinoma in vitro and in vivo. Furthermore, CWP-mediated radiosensitization can trigger immunogenic cell death (ICD) to improve the anti-PD-L1 treatments to inhibit the growth of primary and distant tumors effectively. These results indicate that CWP is a multifunctional nano-sensitizers for radiotherapy and immunotherapy.
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CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Ping Sun,Li Huang,Zimu Li,Yao Yang,Shiman Lu,Nansha Gao,Hongzhong Chen,Xiaowei Zeng,Zhongjian Xie
Ferroptosis is a form of regulated cell death (RCD) induced by excessive lipid peroxidation, representing a promising mechanism for suppressing tumors. Herein, a type of nanoplatform (ODLP-PEGH8) was developed to harness the power of ferroptosis and immunogenic cell death (ICD) for the treatment of breast cancer. To enhance its effectiveness, this project incorporated a pH-responsive PEGH8 peptide onto the surface of the nanoplatform. This modification not only promoted charge reversal within the tumor microenvironment but also improved the cellular uptake efficiency of the nano-system, facilitating intracellular lysosomal escape. Subsequently, ODLP-PEGH8 rapidly degraded under conditions of low pH and exposure to light, resulting in the sequential release of the ferroptosis inducer lapatinib (LTB) and oxaliplatin (OXA). LTB induced ferroptosis and exhibited potent tumor cell-killing effects, while the ODLP-PEGH8, which possessed photothermal properties, worked with OXA to effectively induce ICD within the tumor. This dual approach triggered anti-tumor immune responses and had a substantial impact on tumor immunotherapy. All the results confirm that ODLP-PEGH8 mediates ferroptosis, enhancing the proliferation and infiltration of cytotoxic lymphocytes (CLTs) while demonstrating excellent biological safety in vivo. These findings suggest a promising therapeutic strategy for targeting ferroptosis in cancer treatment.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
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IF 5.3
Minghua Zhang,Xianxian Yao,Jian Xu,Jiaying Song,Shuting Mai,Weichu Zhu,Yichen Zhang,Liangliang Zhu,Wuli Yang
Ferroptosis inhibits tumor growth by iron-dependently accumulating lipid peroxides (LPO) to a lethal extent, which can result from iron overload and glutathione peroxidase 4 (GPX4) inactivation. In this study, we developed biodegradable zwitterionic polymer-cloaked atorvastatin (ATV)-loaded ferric metal–organic frameworks (Fe-MOFs) for cancer treatment. Fe-MOFs served as nanoplatforms to co-deliver ferrous ions and ATV to cancer cells; the zwitterionic polymer membrane extended the circulation time of the nanoparticles and increased their accumulation at tumor sites. In cancer cells, the structure of the Fe-MOFs collapsed in the presence of glutathione (GSH), leading to the depletion of GSH and the release of ATV and Fe 2+ . The released ATV decreased mevalonate biosynthesis and GSH, resulting in GPX4 attenuation. A large number of reactive oxygen species were generated by the Fe 2+ -triggered Fenton reaction. This synergistic effect ultimately contributed to a lethal accumulation of LPO, causing cancer cell death. The findings both in vitro and in vivo suggested that this ferroptosis-inducing nanoplatform exhibited enhanced anticancer efficacy and preferable biocompatibility, which could provide a feasible strategy for anticancer therapy.
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Nano Today
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2024
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IF 13.2
Xiuhua Pan,Jie Yang,Ruixin Kang,Jun Zhang,Zongwei Hu,Ning Yang,Zengyi Liu,Zengguang Jia,Xiawei Zhou,Qi Shen
The induction of ferroptosis in cancer cells has emerged as a promising approach to initiate immunogenic cell death (ICD). However, the limited production of lipid peroxidation (LPO) considerably undermines the effectiveness of ferroptosis. In this work, T7 polypeptide engineered bacterial outer membrane vesicles (T7-OMVs) co-delivering plasmids and melanin nanoparticles (MNPs) are fabricated into nanoclusters (TO@Mp) for LPO amplification. The clustered regularly interspaced short palindromic repeats (CRISPR) system as the gene editing tool can knockdown glutathione peroxides 4 ( GPX4 ) to amplify LPO accumulation. Photothermal MNPs exhibit an intrinsic capacity of up-regulating Acyl-CoA synthetase long chain family member 4 (ACSL4) and generating reactive oxygen species (ROS), thereby cooperating with GPX4 gene knockdown to reinforce ferroptosis. While the TO@Mp NPs augment ICD via synergistic lipid peroxidation induced ferroptosis, the mechanism of proinflammatory response acquired by the RNA-seq analysis also indicates that the nanoclusters activate the toll like receptor (TLR) pathways, thereby coordinately potentiating DCs maturation and T cells immunity to restrain tumor growth and metastasis. Conclusively, the biomimetic bacteria-derived platform for synergistic CRISPR-photothermo modulation represents an appealing way for tumor suppression and immunological therapy, which holds great potential in clinical translation for cancer treatment.
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MATERIALS & DESIGN
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2024
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IF 7.6
Jie Chen,Yan Liu,Yanting You,Ruisi Zhou,Yanchun Li,Xinghong Zhou,Xiaohu Chen,Ying Yang,Jinxiang Chen,Hiu Yee Kwan,Xiaoshan Zhao,Yuyao Wu
Celastrol (CEL) has garnered significant interest for its anti-tumour properties and potential for colorectal cancer (CRC) treatment. However, its clinical use is constrained by its limited bioavailability and potential toxicity. Herein, a biotin-decorated CEL nano-drug delivery system using a zeolitic imidazolate framework (ZIF-8) as a carrier was synthesized, named CEL@ZIF-8@BIO. It exhibits excellent water solubility, efficient loading of CEL, and a high release rate in acidic environments. In vitro experiments demonstrated that CEL@ZIF-8@BIO inhibited proliferation, induced cell cycle arrest in G0/G1 phase, increased ROS production and reduced mitochondrial membrane potential in CRC cells. RNA-Seq analysis indicated that the anticancer mechanism of CEL@ZIF-8@BIO may be linked to ferroptosis as indicated by a significant increase in Fe 2 + levels, oxidative stress, lipid peroxidation, and mitochondrial dysfunction in CRC cells. Furthermore, these effects could be reversed by ferroptosis inhibitor. In vivo research revealed that CEL@ZIF-8@BIO significantly inhibited the growth of CRC tumours and reduced the toxicity associated with CEL treatment. Taken together, the CEL@ZIF-8@BIO nano-drug delivery system shows great promise for CRC therapy due to its improved efficacy and reduced toxicity.
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Journal of Diabetes Research
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2024
·Vol. 2024
·期 1
·7146054
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IF 3.6
Liangxiu Wu,Weicheng Lai,Lanlan Li,Sen Yang,Fengjuan Li,Chen Yang,Xiaobing Gong,Liangyan Wu
Background: Diabetic liver injury is a serious complication due to the lack of effective treatments and the unclear pathogenesis. Ferroptosis, a form of cell death involving reactive oxygen species (ROS)-dependent lipid peroxidation (LPO), is closely linked to autophagy and diabetic complications. Therefore, this study is aimed at investigating the role of autophagy in regulating ferroptosis by modulating the degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4) in diabetic hepatocytes and its potential impact on diabetic liver injury. Methods: Initially, ferroptosis and autophagy were assessed in liver tissues from streptozotocin-induced diabetic rats and in palmitic acid (PA)–treated LO2 cells. Subsequently, the study focused on elucidating the regulatory role of autophagy in mediating ferroptosis through the modulation of ACSL4 expression in PA-treated LO2 cells. Results: The results demonstrated that ACSL4-mediated ferroptosis and inhibition of autophagy were observed in diabetic hepatocytes in vivo and in PA-treated LO2 cells. Additionally, the ferroptosis inhibitor was able to mitigate the PA-induced cell death in LO2 cells. Mechanistically, the stability and expression level of the ACSL4 protein were upregulated and primarily degraded via the autophagy-lysosome pathway in PA-treated LO2 cells. The use of the autophagy inhibitor 3-methyladenine (3-MA) and the inducer rapamycin further demonstrated that autophagy regulated ferroptosis by mediating ACSL4 degradation, highlighting its critical role in diabetic liver injury. Conclusions: These results elucidate the roles of ferroptosis, autophagy, and their interactions in the pathogenesis of diabetic liver injury, offering potential therapeutic targets. Furthermore, they shed light on the pathogenesis of ferroptosis and other diabetic complications.
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Cell Reports Physical Science
·
2024
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IF 7.9
Xu Wang,Tao Han,Xiwei Jiang,Sicen Lin,Xinyu Lou,Xianbao Shi,Zhenguo Cheng,Zhonggui He,Hongzan Sun,Funan Liu,Jin Sun,Mengchi Sun
The application of oncolytic adenoviruses (Ads) is hampered by the inability to target tumor sites via intravenous injection as well as insufficient intratumoral viral replication efficiency. To overcome these challenges, we report bimetallic nanodot-Ad chimeras (Ads@Gd/Fe-NDs) that enable targeted delivery and enhanced Ad replication via cooperativity of autophagy and ferroptosis against tumors. The systemic delivery of Ads@Gd/Fe-NDs leads to a high accumulation of Ads in tumors. Intratumorally released Fe 3+ from chimeras induces ferroptosis within cancer cells, generating reactive oxygen species and activating cellular autophagy. The excessive enrichment of autophagy-induced autophagosomes elevates Ad replication efficiency in infected tumor cells, further resulting in overactivation of autophagy and amplifying autophagy-dependent ferroptosis. In addition, Gd 3+ from Ads@Gd/Fe-NDs is released in response to the tumor microenvironment, serving intratumoral MRI in preclinical tumor-bearing mouse models. Collectively, such a nanodot-oncolytic virus chimera represents a potent translational platform for cancer theranostics.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2024
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IF 5.4
Xieyu Yan,Quanjin Li,Shuai Xiao,Junjie Chen,Wei Song
Promoting ferroptosis in tumor cells has emerged as a promising strategy for cancer therapy. Nonetheless, the heightened antioxidant activity within tumor cells hampers this approach, diminishing its effectiveness and fostering drug resistance. In this study, a new type of sulfasalazine (SAS) loaded nanoframe self-etched Pt-Co nanodendrites (Pt/Co-BNN@SAS) was developed, presenting a novel avenue for inducing ferroptosis in tumor cells by depleting glutathione (GSH) for cancer treatment. Pt/Co-BNN exhibits notable peroxidase (POD) activity, catalyzing the production of abundant oxygen radicals through the consumption of hydrogen peroxide (H 2 O 2 ) and the concurrent depletion of GSH. Simultaneously, the liberated sulfasalazine (SAS) from Pt/Co-BNN@SAS effectively obstructs system xc - , impeding the absorption of cystine by tumor cells and thereby expediting GSH depletion. The expeditious reduction of GSH markedly stimulates the accumulation of lipid peroxides (LPO) and suppresses glutathione peroxidase 4 (GPX4), consequently triggering ferroptosis in bladder cancer cells and inhibiting the migration ability of bladder cancer cells effectively. This research contributes to a more profound comprehension of nano-drug-biological interactions and provides a prospective outlook on treating bladder cancer by instigating ferroptosis in tumor cells through GSH depletion.
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ACS Nano
·
2024
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IF 15.8
Lanlan Fan,Panyu Du,Yaru Li,Xuefei Chen,Fang Liu,Yuning Liu,Alexey M. Petrov,Xin Li,Zheng Wang,Yanjun Zhao
Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G0/G1 phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.
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REDOX REPORT
·
2025
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IF 7.4
Siqi Zhu,Jingyi Ren,Yadong Zhang,Xiaoya Sun,Huanting Pei,Bowen Yin,Ziyi Wang,Zhenao Zhang,Shenghe Li,Ruonan Zhang,Ziqian Zeng,Yuxia Ma
Background Acetaminophen (APAP) is a widely used antipyretic and analgesic agent, and acute exposure can lead to renal injury. Sesamin (Ses) is known for its various health benefits. However, it remains unclear whether Ses exerts a protective effect against APAP-induced kidney injury.Methods In vivo, C57BL/6 mice were pretreated with Ses and injected intraperitoneally with APAP. In vitro, human kidney proximal tubule cells 2 were pretreated with Ses, and then models of kidney injury induced by APAP were established. Kidney damage was evaluated by morphological, inflammation, oxidative stress and protein analyzes.Results Ses significantly improved APAP-induced nephrotoxicity in vitro and in vivo models. Transcriptomic analysis revealed that the differentially expressed genes were enriched in ferroptosis and apoptosis signaling pathways, identifying heme oxygenase 1 (HMOX1) as a core protein. In the Ses-treated group, ferroptosis and apoptosis were significantly inhibited, while HMOX1 was effectively restored. In cell experiments, both the HMOX1 agonist hemin and Ses attenuated ferroptosis and apoptosis. HMOX1 inhibitor Zinc Protoporphyrin significantly eliminated the protective effect of Ses.Conclusion Ses alleviates APAP-induced renal injury by mediating the inhibition of ferroptosis and apoptosis via HMOX1. This study provides a new strategy for the prevention and treatment of drug-induced renal injury.
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