Nature Communications
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2025
·Vol. 16
·期 1
·1-20
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IF 15.7
Bi Guoshu,Liang Jiaqi,Bian Yunyi,Shan Guangyao,Ren Shencheng,Shi Haochun,Huang Xiaolong,Zhu Junkan,Wang Qun,Jiang Wei,Gan Boyi,Zhan Cheng
Ferroptosis, an iron-dependent form of cell death, holds promise for cancer therapy. However, the intricate link between ferroptosis and oncogenic mutations remains unclear. Here we show that SMARCA4, a well-established tumour suppressor whose deficiency is associated with poor prognosis and resistance to treatments, sensitizes non-small cell lung cancer (NSCLC) cells to ferroptosis. Mechanistically, SMARCA4 promotes chromatin accessibility and expression of ALDH16A1. Surprisingly, ALDH16A1 lacks ALDH enzymatic activity, but binds to the anti-ferroptotic oxidoreductase thioredoxin (TXN), facilitating its translocation to the lysosome and subsequent degradation. Meanwhile, ALDH16A1 directly inhibits TXN’s oxidoreductase function by occluding its active site. We also show that either restoring ALDH16A1 levels or inhibiting TXN significantly enhances the effectiveness of chemo/immunotherapy in a ferroptosis-dependent manner in SMARCA4-deficient NSCLC. Collectively, our findings elucidate an intricate SMARCA4-ALDH16A1-TXN stability/function dual regulatory axis that governs ferroptosis and informs a therapeutic strategy for overcoming resistance to chemotherapy or immunotherapy in SMARCA4-deficient NSCLC.
研究领域:
肿瘤学
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分子生物学
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药理学
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细胞生物学
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转化医学
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产品关联
DOI
PubMed
高影响因子
Arabian Journal of Chemistry
·
2024
·
IF 5.3
Chenwei Xiong,JingJing Shang,Zhentang Yu,Junjie Zhang,Kaisong Miao,Changlin Yu,Yong Huang,Yiping Weng,Xindie Zhou
Background Osteoarthritis (OA) is a chronic joint disease characterized by degeneration of the articular cartilage or inflamed joints. Britanin is a guaiacyl-type sesquiterpene lactone possessing anti-inflammatory and antioxidant activities. Methods In this study, western blotting, Reverse-transcription PCR (RT-PCR), and immunofluorescent staining method were used to clarifying the molecular mechanisms of britanin in alleviating chondrocyte ferroptosis. The effect of britanin on reactive oxygen species (ROS) and lipid peroxidation levels in chondrocytes was examined by Dihydroethidium (DHE) stain and fluorescent dye BODIPY581 / 591 C11. The destabilized medial meniscus (DMM) model was used to mimic OA, then britanin was injected into the knee articular cavity. The morphological analysis was performed by hematoxylin and eosin (H&E) staining, Safranin O-Fast green staining and Micro-computed tomography (Micro-CT) analysis. Immunohistochemical analysis and Immunofluorescence assay was conducted to verify the effect of britanin in vivo . Results The results revealed that britanin treatment regulates the expression of chondrocyte extracellular matrix–related factors, such as ADAMTS5, MMP13, SOX9, aggrecan, and COL2A1. Britanin also significantly reversed the influence of interleukin (IL)-1β on the levels of reactive oxygen species and lipid peroxidation and upregulated glutathione peroxidase 4 (GPX4) expression in IL-1β-induced chondrocytes. Erastin could alleviate the effects of britanin on chondrocytes. Moreover, britanin could prevent IL-1β-induced oxidative stress and ferroptosis in chondrocytes. Britanin also upregulated the expression of nuclear factor E2–related factor 2 (Nrf2) in IL-1β-induced chondrocytes, and Nrf2 activator played a similar role as that of britanin in IL-1β-induced chondrocytes. Furthermore, injecting britanin into the knee joints of OA rats alleviated cartilage destruction caused by surgical resection. Conclusions These findings confirmed that britanin can inhibit ferroptosis in OA chondrocytes through the Nrf2-GPX4 pathway. Thus, britanin has the potential to be developed as a drug for OA therapy.
研究领域:
医学
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生物学
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DOI
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
·
IF 5.6
Qianqian Zhao,Ting Wu,Chunming Tang,Jie Li,Min Wu,Jie Wu,Zhiji Wang,Yinxin Zhu,Huae Xu,Xiaolin Li
Combination chemotherapy is considered more effective than monotherapy in enhancing clinical outcomes. Ferroptosis, a unique form of regulated cell death, has been demonstrated to inhibit tumor growth and progression. Consequently, combining ferroptosis with chemotherapy represents a promising and innovative approach to antitumor therapy. In this study, we developed a novel TMTP1-modified biomimetic nanocrystal (TRNC@P + L) for the co-delivery of PTX and LF3, aiming to achieve ferroptosis-combined chemotherapy in gastric cancer. TRNC@P + L, which incorporates a tumor-homing peptide-modified red blood cell membrane, demonstrated efficient tumor targeting, prolonged circulation, enhanced drug bioavailability, and reduced non-specific toxicities of free PTX and LF3. By utilizing the synergistic effects of PTX and LF3, TRNC@P + L combination therapy significantly inhibited tumor growth, as demonstrated by both in vitro and in vivo studies. Mechanistically, TRNC@P + L triggers ferroptosis in tumor cells by downregulating GPX4 expression, the promotion of ROS accumulation, and the enhancement of lipid peroxidation. These processes synergistically enhance the anticancer efficacy of PTX.
研究领域:
肿瘤学
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药理学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
TRANSITION METAL CHEMISTRY
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2025
·
IF 1.7
Feng Qiying,Zhou Lin,Tian Shuang,Yang Jiawan,Liu Yunjun
Herein, we reported the synthesis and characterization of two new iridium(III) complexes [Ir(ppy) 2 (fpp)](PF 6 ) (Ir1a, ppy = 2-phenylpyridine, fpp = 2-(2,2-difluorobenzo[1,3]dioxol-5-yl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(bzq) 2 (fpp)](PF 6 ) (Ir1b, bzq = benzo[h]quinoline) through high resolution mass spectrometry (HRMS), 1 H NMR and 13 C NMR. The cytotoxicity in vitro of Ir1a and Ir1b on normal NIH3T3 cells and cancer SGC-7901, A549, SK-Hep1 cells was tested using MTT (3-(4,5-dimethylthiazole-2-yl)-diphenyltetrazolium bromide) method. Ir1a exhibits high cytotoxicity on SGC-7901 cells (IC 50 = 2.7 ± 0.7 µM), whereas Ir1b shows moderate cytotoxicity toward the selected cancer cells. The ROS content was investigated using a fluorescence probe of 2′,7′-dichlorodihydrofluorescein diacetate (DCHF-DA), the results show that Ir1a and Ir1b elevate ROS content. The co-localization and the change of mitochondrial membrane potential were explored. Apoptotic studies using Annex V/PI double staining method demonstrate that Ir1a and Ir1b can efficiently cause apoptosis. Ir1a and Ir1b inhibit the cell proliferation at the G2/M period. Additionally, lipid peroxidation and downregulation of ferritin protein suggest that Ir1a and Ir1b can trigger ferroptosis.
研究领域:
药理学
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肿瘤学
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生物化学
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产品关联
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Huilan Zhuang,Lun Wang,Sijie Shao,Haitong Jing,Panpan Xue,Tingjie Bai,Jinpeng Deng,Xuemei Zeng,Xian Qin,Shuangqian Yan
Ferroptosis has emerged as a novel approach to suppress tumor growth through the iron-dependent accumulation of lipid peroxides, providing new opportunities for cancer therapy. However, the effectiveness of ferroptosis is impeded by the substantial neutralization of reactive oxygen species (ROS), generated through the Fenton reaction, by the high level of glutathione in cancer cells. Here we report a titanium metal–organic frameworks (MOFs)-derived method to create black TiO 2 nanoparticles with excellent photocatalytic performance. The nanoparticle has a narrow bandgap of 1.02 eV, multiple discrete gap states, and a high density of oxygen vacancies (46.2 %), facilitating ROS generation under 1064-nm light irradiation. When coated with a tannic acid/Fe 3+ layer, the resulting nanocomposite possesses the ability to deplete glutathione concentration, preventing the newly generated ROS from being neutralized and promoting ferroptotic cancer cell death. Complemented by photothermal and chemodynamic effects, in vivo experiments demonstrate a high tumor inhibition rate of 89.8 %. The utilization of MOF-derived nanomaterials represents a universal strategy, offering a solution for ferroptosis-based therapy in solid tumors and contributing to the development of smart, optically active materials with diverse applications in biological contexts.
研究领域:
生物医学
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材料科学
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肿瘤学
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产品关联
DOI
高影响因子
Acta Pharmaceutica Sinica B
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2025
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IF 14.6
Dan Feng,Jian Zhang,Huanmin Niu,Xiaoxue Zheng,Mengqi Jia,Qiqi Lu,Jing Wang,Wenxue Guo,Qi Sun,Huiqing Yuan,Hongxiang Lou
The elevated polyamines, amine-rich molecules with diverse functions in pathophysiology processes, are implicated in contributing to tumorigenesis and progression. Whether and how they affect the efficacy of chemotherapy is incompletely understood. Our screening assays reveal that the supplement with a low dose of spermidine (Spd), one of the polyamines, enhances ferroptosis in prostate cancer cells as evidenced by increased lipid peroxidation and intracellular Fe 2+ levels in vitro . Combination treatment with Spd and a low dose of ferroptosis inducer erastin synergistically augments anti-tumor efficacy with undetectable toxicity in mice. Analysis of RNA-seq data indicates that heme oxygenase 1 (HMOX1), an enzyme that catalyzes the cleavage of heme to release Fe 2+ , is significantly upregulated in response to Spd and erastin cotreatment. Spd mediated the hypusine modification of the eukaryotic initiation factor 5A (EIF5A) promotes the translation of the nuclear factor erythroid 2-related factor 2 (NRF2), subsequently leading to elevation of HMOX1. Moreover, Spd and erastin significantly inhibit proteasome activity which results in a decrease in proteasomal degradation of NRF2, although many proteasome-related genes are induced either by Spd or Spd plus erastin. Thus, in addition to its pro-oncogenic activity, the supplement of Spd improves antitumor activity in combination with ferroptosis inducers and offers an optional approach to cancer treatment.
研究领域:
肿瘤学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
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2024
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IF 5.3
Fanqi Meng,Lei Chen,Haoran Chen,Meili Shen,Guangyi Wang,Yulei Chang
Combined phototherapy with other therapeutic strategies can improve the therapeutic outcomes of tumors and reduce the side effects. However, shaping multiple modalities for combination therapy remains challenging. Herein, multiple stimuli-responsive drug-loaded micelles are presented, which are self-assembled from cypate-conjugated pH-sensitive poly(ethylene glycol)–poly(2-(diisopropylamino) ethyl methacrylate)–poly(2-aminoethyl methacrylate hydrochloride) and redox-responsive poly(glycidyl methacrylate)–poly(propylene sulfide) copolymer and loaded with chemo agents doxorubicin (DOX) and sorafenib (SRF, also a ferroptosis inducer) for enhanced tumor therapy. The DOX and SRF chemo drugs were encapsulated into the hydrophobic core of PPS and PDPA to enable multiple stimuli-responsive controlled drug delivery. In vivo and in vitro experiments are carried out to investigate the potential application for controlled drug release and systemic chemo-phototherapy. This study highlights the rational design of cypate-based drug-loaded micelles, offering multiple stimuli-responsive drug releases and synergistic photo-, ferro-, and chemotherapy in colorectal cancer.
研究领域:
肿瘤学
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药剂学
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生物医学工程
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产品关联
DOI
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
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2024
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IF 4.2
Hongmin Lu,Yue Zhang,Xin Zhang,Ruoqi Wang,Tiantian Guo,Qi Wang,Hongjing Zhao,Mingwei Xing
Environmental pollution caused by arsenic or its compounds is called arsenic pollution. Arsenic pollution mainly comes from people mining and smelting arsenic compounds. In addition, arsenic compounds' widespread use and production of arsenic-containing pesticides, arsenic-rich water used to irrigate farms, or high arsenic levels in foods caused by coal burning are all sources of arsenic contamination. Arsenic contamination poses a significant threat to global public health. It is reported that exposure to arsenic can induce severe renal injury. However, the underlying mechanism needs to be clarified. In this study, the arsenic exposure model in vivo and in vitro was used to explore the mechanism of arsenic-induced renal injury, especially the role of ferroptosis and its regulatory mechanism, and then to evaluate its anti-pollution effect by supplementing zinc. The results showed that arsenic significantly induced ferroptosis, characterized by up-regulating the expression of YAP and TFR in kidney and CIK cells and then increasing the levels of Fe 2+ and ROS, lipid peroxidation, and iron metabolism. Microscopic observation revealed the shrinkage of mitochondria and the increase in membrane density. In addition, molecular docking and inhibitor experiments further confirmed that arsenic is involved in the process of ferroptosis by activating YAP and TFR. These results clarify the harmful effects of arsenic on carp kidneys and its mechanism and highlight the critical interactions between the YAP-TFR pathway, ROS, and ferroptosis. Importantly, this study found that zinc can reduce ferroptosis caused by the arsenic-activated YAP-TFR pathway by inhibiting YAP activation and lipid peroxidation.
研究领域:
环境科学
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毒理学
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水生生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
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2021
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IF 6.684
Zhu Yiming,Zhang Chihao,Huang Mingzhe,Lin Jiayun,Fan Xiao,Ni Tao
Hepatic stellate cells (HSCs) are activated by inflammatory mediators to secrete extracellular matrix for collagen deposition, leading to liver fibrosis. Ferroptosis is iron- and lipid hydroperoxide-dependent programmed cell death, which has recently been targeted for inhibiting liver fibrogenic processes. Tripartite motif-containing protein 26 (TRIM26) is an E3 ubiquitin ligase that functions as a tumor suppressor in hepatocellular carcinoma, while little is known about its function in liver fibrosis. In the present study, the differential expression of TRIM26 in normal and fibrotic liver tissues was examined based on both online databases and specimens collected from patient cohort. The effects of TRIM26 on HSCs ferroptosis were examined in vitro through evaluating cell proliferation, lipid peroxidation, and expression of key ferroptosis-related factors. In vivo function of TRIM26 in liver fibrosis was examined based on CCl4-induced mice model. We found that TRIM26 was downregulated in fibrotic liver tissues. The overexpression of TRIM26 inhibited HSCs proliferation, promoted lipid peroxidation, manipulated ferroptosis-related factor expressions, and counteracted the effect of iron inhibitor deferoxamine. Moreover, TRIM26 physically interacted with solute carrier family-7 member-11 (SLC7A11), a critical protein for lipid reactive oxygen species (ROS) scavenging, and mediated its ubiquitination. In addition, TRIM26 overexpression induced HSCs ferroptosis and mitigated CCl4-induced liver fibrosis in mice. In conclusion, TRIM26 promotes HSCs ferroptosis to suppress liver fibrosis through mediating the ubiquitination of SLC7A11. The TRIM26-targeted SLC7A11 suppression can be a novel therapeutic strategy for liver fibrosis.
研究领域:
分子生物学
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细胞生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Ke Xue,Yongfei Zhao,Saidong Sun,Yuanhang Li,Jiankang Liang,Zhengjian Qi
Severe ferroptosis is a non-apoptotic iron-dependent cell death pathway, and extreme hypoxia and anomalous iron metabolism in tumors critically suppress the efficacy of ferroptosis therapy. Overcoming tumor hypoxia while facilitating ferroptosis is an extremely challenging task. Herein, the photosensitizer named BOTTQ with specific targeting of lipid droplet (LD) was synthesized by increasing the tail chain length of triphenylamine. The addition of alkoxy chains optimized the molecular structure and fostered inter-system crossing and type I reactive oxygen species (ROS) generation. Besides, BOTTQ yielded large amounts of type I ROS under light excitation oxidize efficiently polyunsaturated fatty acids in lipid monolayer of LD and contribute to the formation of ferroptosis substrate. Meanwhile, the generation of type I ROS accelerated the Fenton reaction, thus effectively boosting the occurrences of ferroptosis. Furthermore, the successful encapsulation of BOTTQ into DSPE-PEG-MAL material not only elevates the stable type of nanoparticle colloids, but the MAL moiety can deplete the functional thiols of glutathione in a mild environment, which leads to glutathione failure and facilitates ferroptosis. Thus tumor-specific ferroptosis-inducing strategy offers a universally applicable therapy with the capacity to enhance type I ROS production and effectively contain tumorigenesis.
研究领域:
生物医学工程
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肿瘤学
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药理学
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产品关联
DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2022
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IF 11.467
Chencheng Xue,Hui Zhang,Xuan Wang,Haoyu Du,Lu Lu,Yang Fei,Yanan Li,Yuchen Zhang,Menghuan Li,Zhong Luo
Nanotechnology-enabled ferroptosis therapy is an emerging paradigm for tumor treatment, but amplifying ferroptotic damage in tumor cells in a safe and selective manner is still challenging, which severely hinders its clinical translation. In this study, we constructed a bio-inspired protein nanocomplex based on natural-occurring bovine serum albumin (BSA) and ferritin for efficient tumor elimination via cooperatively enhanced ferroptosis therapy. The long-circulating BSA molecules provided multiple anchoring points for the efficient loading of the GPX4-inhibiting ferroptosis inducer (1S, 3R) RAS-selective lethal 3 (RSL3), which was further complexed with ferritin via acidity-responsive glutaraldehyde linkers. The ferritin moieties may not only bind to transferrin receptor 1 overexpressed on tumor cell membrane for targeted endocytic uptake but also be degraded in lysosomes to induce iron overload, which could substantially promote the lipid peroxidation in tumor cells and cooperate with the glutathione peroxidase 4 (GPX4)-inhibiting capability of RSL3 to induce pronounced ferroptosis. The in vitro and in vivo results collectively demonstrated that the albumin-ferritin-based nanocomplex could present superior antitumor effects with no obvious adverse effects, which may open new avenues for the clinical translation of ferroptosis-dependent therapeutic modalities.
研究领域:
肿瘤学
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纳米医学
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生物材料学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
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2023
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IF 15.1
Xinyu Miao,Yinyan Yin,Yulian Chen,Wenhui Bi,Yuncong Yin,Sujuan Chen,Daxin Peng,Lizeng Gao,Tao Qin,Xiufan Liu
Influenza virus with numerous subtypes and frequent variation limits the development of high-efficacy and broad-spectrum antiviral strategy. Here, a novel multi-antiviral metastable iron sulfides (mFeS) against various influenza A/B subtype viruses is developed. This work finds that mFeS induces high levels of lipid peroxidation and •OH free radicals in the conservative viral envelope, which depends on Fe 2+ . This phenomenon, termed as a viral ferroptosis, results in the loss of viral infectibility and pathogenicity in vitro and in vivo, respectively. Furthermore, the decoction of mFeS (Dc(mFeS)) inhibits cellular ferroptosis-dependent intracellular viral replication by correcting the virus-induced reprogrammed sulfur metabolism, a conserved cellular metabolism. Notably, personal protective equipment (PPE) that is loaded with mFeS provides good antiviral protection. Aerosol administration of mFeS combined with the decoction (mFeS&Dc) has a potential therapeutic effect against H1N1 lethal infection in mice. Collectively, mFeS represents an antiviral alternative with broad-spectrum activity against intracellular and extracellular influenza virus.
研究领域:
病毒学
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药理学
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材料科学
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治疗学
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产品关联
DOI
PubMed
高影响因子
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