Journal of Materials Chemistry B
·
2022
·Vol. 10
·期 30
·5784-5795
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IF 7.571
Jingbo Lin,Jiaxin Zhang,Kuang Wang,Shengdi Guo,Wuli Yang
Ferroptosis, as a form of cell death different from apoptosis, is very promising for the treatment of cancer in nonapoptotic systems. Since iron is a key component in the induction of ferroptosis in cells, the use of iron-based nanomaterials in treating cancer through ferroptosis is of great significance. Therefore, in this study, magnetic nanoparticles (MNP) were coated with the zwitterionic polymer poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), and then loaded with sorafenib (SRF) to obtain drug-loaded composite nanoparticles MNP@PMPC-SRF. Fe3O4 provided a large number of ferric/ferrous ions as an iron source, releasing Fe2+ for the regulation of the ferroptosis process and enhancing the effect of the induced cellular ferroptosis on the treatment of colon cancer with SRF. The zwitterionic polymer PMPC effectively extended the blood circulation time, resulting in an enhanced tumor accumulation of the nanodrug. MNP@PMPC-SRF exhibited good biocompatibility for in vivo application and showed an excellent tumor inhibitory effect on HCT116 tumor-bearing nude mice.
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ACTA BIOCHIMICA ET BIOPHYSICA SINICA
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2026
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IF 4.5
Xiaojun Ren,Yaqiong Zhang,Xiaoxuan Zhou,Saijun Xiao,Kai Huang,Yingjie Dai,Xunjun Yang,Hezhi Fang,Jianxin Lyu,Zhengquan Yang,Minghua Jiang
7-Dehydrocholesterol (7-DHC) has recently emerged as an endogenous suppressor of lipid peroxidation/ferroptosis; however, its function in nutrient-poor microenvironments remains undefined. Here, we demonstrate that activated c-Myc directly occupies the DHCR7 promoter in pancreatic ductal adenocarcinoma (PDAC) cells, transcriptionally upregulating DHCR7, which converts 7-DHC into cholesterol, thereby fuelling PDAC cell proliferation. Under glucose deprivation, DHCR7 deletion triggers pronounced ferroptosis in PDAC cells, an effect that is sharply attenuated when glucose is supplemented. Mechanistically, DHCR7 inhibition drives 7-DHC accumulation, which plays a dual role: it traps free radicals (anti-ferroptosis) and yet simultaneously depletes the antioxidant pool (pro-ferroptosis), with the net outcome dictated by glucose availability. The antioxidant pool maintained by glucose is required to counteract the pro-peroxidation effects of 7-DHC; once glucose is limited, the radical-trapping-mediated anti-ferroptosis function of 7-DHC becomes negligible. Furthermore, glucose restriction in vitro and a low-glucose diet in vivo both sensitized PDAC cells to DHCR7 inhibition-triggered lipid peroxidation, which allows accelerated cell death or suppressed tumor growth. Collectively, 7-DHC, negatively regulated by the c-Myc/DHCR7 axis, promotes lipid peroxidation and ferroptosis in glucose-deficient PDAC tumors, revealing a metabolic vulnerability that can be exploited for therapy.
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iScience
·
2023
·Vol. 26
·期 12
·108340-108340
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IF 5.8
Mengxing Cai,Jingwen Luo,Chunxiu Yang,Xiaopeng Yang,Cheng Zhang,Lixin Ma,Yibin Cheng
Sorafenib induces ferroptosis, making it a useful treatment against advanced liver hepatocellular carcinoma (LIHC). However, sorafenib resistance is extremely common among LIHC patients. Here, we used a comprehensive approach to investigate the effects of ABHD12, which regulates tumorigenesis and sorafenib resistance in LIHC. We validated ABHD12 expression was upregulated in LIHC tissue, which correlated with worse overall survival and related to tumor size or stage. ABHD12 facilitated a pro-tumorigenic phenotype involving increased cell proliferation, migration, and clonogenicity as well as sorafenib resistance. Knockout of ABHD12 sensitized liver cancer cells to sorafenib-induced ferroptosis. Co-delivery of sorafenib and ABHD12 inhibitor into a nude mouse model enhanced therapeutic efficacy for LIHC. Our study demonstrates that ABHD12 contributes to tumor growth and sorafenib resistance in liver cancer, which indicate the promising potential of ABHD12 in diagnosis and prognosis as well as highlight the potential therapeutic applications for co-delivery of sorafenib and ABHD12 inhibitor.
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BIOMEDICINE & PHARMACOTHERAPY
·
2024
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IF 6.9
Yuwei Yang,Yuanfang Chen,Haikang Tang,Ziqi Zhang,Xiaoliang Zhou,Wenqing Xu
Conventional antineoplastic therapies cause severe normal tissue damage and existing cytoprotectants with acute toxicities or potential tumor protection limit their clinical application. We evaluated the selective cytoprotection of 2,2-dimethylthiazolidine hydrochloride in this study, which could protect normal tissue toxicity without interfering antineoplastic therapies. By using diverse cell lines and A549 xenograft model, we discovered a synthetic aminothiol 2,2-dimethylthiazolidine hydrochloride selectively diminished normal cellular ferroptosis via SystemXc-/Glutathione Peroxidase 4 pathway upon antineoplastic therapies without interfering the anticancer efficacy. We revealed the malignant and non-malignant tissues presenting different energy metabolism patterns. And cisplatin induces disparate replicative stress, contributing to the distinguishable cytoprotection of 2,2-dimethylthiazolidine in normal and tumor cells. The compound pre-application could mitigate cisplatin-induced normal cellular mitochondrial oxidative phosphorylation (OXPHOS) dysfunction. Pharmacologic ablation of mitochondria reversed 2,2-dimethylthiazolidine chemoprotection against cisplatin in the normal cell line. Combined, these results provide a potential therapeutic adjuvant to selectively diminish normal tissue damages retaining antineoplastic efficacy.
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Cell Death Discovery
·
2024
·Vol. 10
·期 1
·1-12
·
IF 6.1
Fan Chunhong,Wu Haotian,Du Xin,Li Canjun,Zeng Wenping,Qu Lili,Cang Chunlei
Cancer stem cells (CSCs) are a sub-population of cells possessing high tumorigenic potential, which contribute to therapeutic resistance, metastasis and recurrence. Eradication of CSCs is widely recognized as a crucial factor in improving patient prognosis, yet the effective targeting of these cells remains a major challenge. Here, we show that the lysosomal cation channel TRPML1 represents a promising target for CSCs. TRPML1 is highly expressed in breast cancer cells and exhibits sensitivity to salinomycin, a drug known to selectively eliminate CSCs. Pharmacological inhibition and genetic depletion of TRPML1 promote ferroptosis in breast CSCs, reduce their stemness, and enhance the sensitivity of breast cancer cells to chemotherapy drug doxorubicin. The inhibition and knockout of TRPML1 also demonstrate significant suppression of tumor formation and growth in the mouse xenograft model. These findings suggest that targeting TRPML1 to eliminate CSCs may be an effective strategy for the treatment of breast cancer.
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Autophagy
·
2024
·
IF 14.6
Xin Chen,Andrey S. Tsvetkov,Han-Ming Shen,Ciro Isidoro,Nicholas T. Ktistakis,Andreas Linkermann,Werner J.H. Koopman,Hans-Uwe Simon,Lorenzo Galluzzi,Shouqing Luo,Daqian Xu,Wei Gu,Olivier Peulen,Qian Cai,David C. Rubinsztein,Jen-Tsan Chi,Donna D. Zhang,Changfeng Li,Shinya Toyokuni,Jinbao Liu,Jong-Lyel Roh,Enyong Dai,Gabor Juhasz,Wei Liu,Jianhua Zhang,Minghua Yang,Jiao Liu,Ling-Qiang Zhu,Weiping Zou,Mauro Piacentini,Wen-Xing Ding,Zhenyu Yue,Yangchun Xie,Morten Petersen,David A. Gewirtz,Michael A. Mandell,Charleen T. Chu,Debasish Sinha,Eftekhar Eftekharpour,Boris Zhivotovsky,Sébastien Besteiro,Dmitry I. Gabrilovich,Do-Hyung Kim,Valerian E. Kagan,Hülya Bayir,Guang-Chao Chen,Scott Ayton,Jan D. Lünemann,Masaaki Komatsu,Stefan Krautwald,Ben Loos,Eric H. Baehrecke,Jiayi Wang,Jon D. Lane,Junichi Sadoshima,Wan Seok Yang,Minghui Gao,Christian Münz,Michael Thumm,Martin Kampmann,Di Yu,Marta M. Lipinski,Jace W. Jones,Xuejun Jiang,Herbert J. Zeh,Rui Kang,Daniel J. Klionsky,Guido Kroemer,Daolin Tang
Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.Abbreviation: 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green™ SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy.
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LIFE SCIENCES
·
2024
·
IF 5.2
Qiuwen Fei,Jian Zhang,Liangqiong Chen,Manqi Shi,Qinglan Wang,Feifan Xu,Jiahai Shi,Yongwei Qin
Background Mycobacterium tuberculosis infection triggers various forms of host cell death, including ferroptosis in lung epithelial cells; YY1, a critical transcription factor, plays a pivotal role in regulating ferroptosis, however, the underlying mechanisms are not fully understood. Methods To investigate Mycobacterium marinum ( M.marinum )infection in lung epithelial cells A549 and H1299, we utilized flow cytometry to evaluate cell death and measure reactive oxygen species (ROS). Colony-forming unit (CFU) assays determined the intracellular bacterial load. Ferroptosis was analyzed using a specific detection kit to measure malondialdehyde (MDA) and glutathione (GSH) levels. The interaction between the transcription factor YY1 and the iNOS promoter was assessed through a dual-luciferase reporter assay. Results M.marinum induced ferroptosis in lung epithelial cells through invasion. This effect is most pronounced at 8 h of infection and decreases over time but increased with a higher multiplicity of infection (MOI). YY1 knockdown decreases the expression of SLC7A11 and GPX4, attenuates cellular ferroptosis, while YY1 overexpression has the opposite phenomenon, enhancing the expression of bactericidal molecules such as iNOS and MPEG1, thereby markedly reducing the intracellular bacterial load. We identified substantial binding of YY1 to the iNOS promoter region (−655 to −1018 bp), enhancing mycobactericidal activity in YY1-overexpressing cells. Conclusions Our study demonstrates that YY1 inhibits ferroptosis induced by Mycobacterium marinum infection and reduces intracellular bacterial proliferation in lung epithelial cells. These findings provide a crucial basis for developing anti-tuberculosis therapies that target YY1 modulation, potentially offering new clinical avenues for the treatment of tuberculosis.
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Cell Reports
·
2025
·
IF 6.9
Wenyi Yang,Xiang Chen,Chunyan Yang,Yanqing Mao,Wei Zhuang,Yunshan Xiao,Xueqin Zhang,Zhimin Ou,Ying Chen
Myelin sheath is essential for the maintenance of neural system functions. The mediator complex (MED) is associated with neurodegenerative diseases. Mutation of the MED subunit Med20 leads to abnormal brain development, but whether Med20 modulates myelination remains unknown. In this study, we report that Med20 is an important modulator of myelination in the peripheral nervous system. Loss of Med20 in Schwann cells (SCs) induces ferroptosis, thus impairing myelination. The functions of Med20 in SCs are mediated by its downstream target DDB1. DDB1 controls SC ferroptosis by regulating Hmox1 through a “ DDB1-UHRF1-BACH1-Hmox1 ” transcription regulation axis and its direct interaction and subsequent simultaneous ubiquitination of the HO-1 protein. HO-1 inhibitor ZnPP or ferroptosis inhibitor Fer-1 is sufficient and efficient for antagonizing ferroptosis in SCs and restoring myelination in Med20 -deficient mice. The results of our study reveal that Med20 is an important regulator in the network that controls myelination in the peripheral nervous system.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Xie-Huang Sheng,Lin-Song Teng,Xin-Hui Wang,Li-Qi Jiang,Xue-Cheng Sun,Jin-Long Mao,Lei Zhang
Cardiovascular diseases arise from intertwined cell-death and stress-response pathways, underscoring the need for therapeutics that extend beyond single-target mechanisms. Seeking drug-repurposing opportunities within existing cardiovascular agents, we screened clinically explored compounds for unrecognized cytoprotective activity and identified the hERG/Kv11.1 activator NS-1643—originally developed as an antiarrhythmic candidate—as a potent ferroptosis inhibitor. NS-1643 broadly suppressed GPX4 inhibitor–induced ferroptotic death across diverse cell types, whereas other hERG modulators were inactive, and neither pharmacologic blockade nor genetic silencing of hERG altered its efficacy, demonstrating that its protective mechanism is independent of ion-channel modulation. Mechanistic profiling showed that NS-1643 does not restore canonical ferroptosis-defense systems, but instead operates as a direct lipid-peroxyl radical trapper, supported by radical-scavenging assays and density functional theory revealing an energetically favorable hydrogen-atom transfer mediated by its ortho-amino–phenolic motif. In a murine model of doxorubicin (DOX) cardiotoxicity, NS-1643 markedly improved survival, preserved systolic performance, and reduced myocardial injury, fibrosis, and 4-HNE accumulation, whereas the comparator hERG agonist NS-3623 conferred no benefit. These findings reposition NS-1643 as a dual-mechanism, ferroptosis-targeting cardioprotective agent and illustrate how drug repurposing can reveal multi-target therapeutic potential within existing cardiovascular chemical space, offering a promising strategy to mitigate anthracycline-induced cardiac injury.
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BIOMATERIALS
·
2026
·
IF 13.6
Jinwu Wang,Chao Lou,Zhihao Shen,Jin Yang,Hongyi Jiang,Heng Yu,Yu Zhang,Yangbo Li,Hua Chen,Aimin Wu,Zengjie Zhang,Leyi Cai,Wenhao Zheng
Osteoarthritis (OA) progression is driven by persistent oxidative stress and ferroptosis, which erode chondrocyte viability and extracellular matrix integrity. Although mesenchymal stem cell–derived exosomes (MSC-EXO) hold regenerative promise, their native cargo lacks the adaptability to withstand such a hostile microenvironment, limiting therapeutic efficacy. Here, we demonstrated a synergistic strategy involving reverse-adaptation and engineered MSC exosomes against ferroptosis in osteoarthritis. Firstly, the reverse-adaptation strategy in which OA-like oxidative stress was harnessed to precondition MSCs, thereby identifying miR-142a-3p as a key therapeutic mediator in tert -butyl hydroperoxide (TBHP)-modified exosomes (T-EXO). Subsequently, we engineered MSC-derived exosomes via miR-142a-3p electroporation (EXO miR−142a−3p ) with unique anti-ferroptosis and antioxidative properties. EXO miR−142a−3p were markedly enriched with miR-142a-3p, which directly targeted the GSK3β/Nrf2/SLC7A11 axis to suppress ferroptosis and reactive oxygen species (ROS) accumulation. Compared to naive EXO, EXO miR−142a−3p exhibited superior protection against cartilage matrix degradation and significantly slowed OA progression in a murine model. By integrating these engineered exosomes into a biodegradable, cartilage-targeted, and lubricious microsphere platform, we achieved sustained, site-specific delivery that amplified therapeutic durability and efficacy. This platform robustly mitigated extracellular matrix (ECM) degradation, ferroptosis, and oxidative stress in vitro, and conferred significant cartilage protection in a destabilization of medial meniscus (DMM)-induced OA model via efficient, prolonged intra-articular release. Collectively, this innovative approach not only provides potent cartilage protection in preclinical models but also establishes a paradigm for precision, microenvironment-adaptive regenerative therapies for OA and other degenerative diseases.
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Materials Today Bio
·
2026
·
IF 11
Mengen Guo,Wenjie Xu,Yanjin Peng,Yucheng Tang,Xinyan Hao,Tiantian Tang,Xinying Liu,Hai Huang,Ruyue Han,Junyong Wu,Daxiong Xiang
Bacterial combination therapy offers immense promise for treating aggressive "cold" solid tumors, such as triple-negative breast cancer (TNBC). However, the clinical translatability of traditional genetic engineering is often hampered by operational complexity and genetic instability. Here, we developed A-SPB—a non-genetically engineered, multi-functional living bioreactor based on Shewanella oneidensis MR-1 (SO), surface-modified with Prussian blue (PB) nanoparticles and attenuated via deoxycholic acid (DA) treatment. This platform serves as an in situ metabolic factory that "hijacks" the sulfur-metabolism within the hypoxic tumor microenvironment. By actively depleting cysteine, A-SPB not only starves the glutathione (GSH) synthesis pathway but also generates hydrogen sulfide (H 2 S) to inhibit the transsulfuration bypass, leading to a dual-pronged collapse of the GSH/GPX4 antioxidant axis and triggering robust tumor ferroptosis. This metabolic sensitization is further amplified by the PB-mediated photothermal therapy (PTT), which generates localized hyperthermia and excessive reactive oxygen species (ROS). Notably, the PTT serves as a dual-functional "bio-switch": it promotes acute tumor ablation while simultaneously triggering bacterial self-lysis to ensure biosafety. This programmed lysis releases a synergistic cocktail of bacterial PAMPs and tumor-derived DAMPs, which effectively remodels the immunosuppressive TME and initiates a potent systemic antitumor immune response. By integrating metabolic reprogramming, sensitized ferroptosis, and on-demand immune activation through simple surface engineering, this study provides a highly translatable and safe paradigm for the next generation of living bacterial therapeutics.
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PHYTOMEDICINE
·
2026
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IF 8.3
Hongjin Wang,Jingjing Li,Xiaogang Xu,Yixi Zeng,Guofeng Shi,Lanyue Zhang,Junxia Zheng,Hui Li
Background Skin photo-aging induced by ultraviolet radiation (UVR) leads to aesthetic alterations, structural degradation, and loss of barrier function. Ferroptosis has been implicated upon UVR stress but the driving modifiers remain largely undefined. Naringin has been reported to exert protective effects against UVR damage, however, the underlying mechanisms remain incompletely understood. Purpose To explore the driving factors of UVR-induced ferroptosis and to comprehensively evaluate the effects and underlying mechanisms of naringin in repressing UVR-induced photo-aging. Methods A mouse model in which the dorsal skin, as well as a cell model using HaCaT keratinocytes, were exposed to UVR to simulate daily sun exposure. Lentivirus-mediated knockdown, ChIP-seq, and RNA-seq analysis were used to evaluate the role of NR4A1 in UVR-induced ferroptosis. RNA-seq and metabonomics were performed to elucidate the underlying mechanisms of naringin against photo-aging. Molecular dynamics simulations/DARTS/CETSA, and co-IP assays were employed to investigate the mechanism by which naringin regulates NR4A1 expression. Results Reduction of NR4A1 leads to excessive lipid metabolism and initiates ferroptosis in UVR-induced photo-aging. Naringin directly binds to NR4A1, enhancing its stability by preventing ubiquitin-mediated degradation, transcriptionally represses EGR1 and LDLR expression, thereby suppressing lipid peroxidation and ferroptotic damage. Remarkably, both genetic deficiency and pharmacological inhibition of NR4A1 across diverse models abolish the effects of naringin against photo-aging. Conclusion Our findings emphasize the critical role of NR4A1 in ferroptosis driven by dysregulated lipid metabolism and reveal the therapeutic potential of targeting NR4A1 with naringin in UVR-induced photo-aging, as well as in the other relevant lipid metabolism dysfunction disorders.
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