CHEMICAL RESEARCH IN TOXICOLOGY
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2024
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IF 3.7
Xiuhao Yu,Shaokun Chen,Hailin Wang
Chlorobenzoquinones (CBQs) are a class of emerging water disinfection byproducts that pose significant risks to public health. In this study, we found that three CBQs (tetrachloro-1,4-benzoquinone, 2,5-dichloro-1,4-benzoquinone, and 2-chloro-1,4-benzoquinone) can significantly aggravate cell death caused by Ras-selective lethal small molecule 3 (RSL3). Further study showed that the cell death caused by CBQs, either alone or in combination with RSL3, was related to iron accumulation and GPX4 inactivation, suggesting the occurrence of ferroptosis. Furthermore, reactive oxygen species are found to play a potential key role in mediating the toxicity of CBQs in CBQs and RSL3-induced ferroptosis. These findings will be helpful in understanding the toxic mechanism of CBQs to mammalian cells.
研究领域:
毒理学
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细胞生物学
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环境科学
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公共卫生
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PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2025
·
IF 6.8
Chao Zhao,Xiaoyan Huang,Zhuoyang Wu,Wanlu Sun,Yi Pan,Yi Liu
The activatable upconversion photosensitizer is a type of photosensitizer that can be activated in the tumor microenvironment (TEM) to achieve precise photodynamic therapy. As an inducer of ferroptosis, it is difficult for RSL3 to target tumor cells accurately and may be toxic to normal tissues. Thus, we developed a pH-responsive self-assembled near-infrared upconversion photosensitizer (Re-NPs) and encapsulated RSL3 drugs (RSL3@Re-NPs) to induce ferroptosis synergistically. The RSL3@Re-NPs can effectively release RSL3 under acidic conditions in TEM, and they can generate singlet oxygen under 808 nm. Through the combination of RSL3 and a photosensitizer, the specific release of the drug and the accumulation of lipid peroxide were realized. In vitro and in vivo results showed that RSL3@Re-NPs had good biocompatibility and significantly inhibited tumor cell proliferation by inducing cell ferroptosis. This combination strategy provides new ideas and methods for tumor treatment, which is expected to improve the efficacy of tumor treatment and reduce side effects.
研究领域:
生物医学工程
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纳米医学
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光动力治疗
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癌症生物学
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药物递送系统
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PubMed
高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
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2025
·Vol. 30
·期 1
·1-27
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IF 10.2
Chen Dejian,Xie Fei,Mo Yimei,Qin Dan,Zheng Binjiao,Chen Lingyan
Background The classical ferroptosis activator RSL3 targets enzymes with nucleophilic active sites, primarily acting on glutathione peroxidase 4 (GPX4) to trigger ferroptosis. Recent studies identify RSL3 as a potential pro-apoptotic agent. However, the mechanism by which RSL3 induces apoptosis during ferroptosis remains elusive. Poly(ADP-ribose) polymerase (PARP1) determines cell fate in response to DNA damage, where its loss or cleavage by activated caspase-3 induces apoptosis to attenuate tumor progression. We elucidate a novel mechanism underlying PARP1 regulation, encompassing both its caspase-dependent cleavage and full-length depletion during RSL3-mediated ferroptosis-apoptosis crosstalk. Methods To investigate the role of RSL3 during ferroptosis, we treated several cancer cells of different histological types with varying doses of RSL3 to induce apoptosis. The regulatory proteins of PARP1 were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The N 6 -methyladenosine (m 6 A) modification level of PARP1 was determined by m 6 A RNA immunoprecipitation (MeRIP)-qPCR analysis. Additionally, an RNA immunoprecipitation (RIP)-qPCR assay was performed to identify the target protein of the m 6 A site of PARP1. Furthermore, we established a mouse xenograft model of PARP inhibitor (PARPi)-resistant cells to analyze the effect of RSL3 on PARPi-resistant tumor growth. Results RSL3 triggers two parallel apoptotic pathways via increasing reactive oxygen species (ROS) production during ferroptosis: (1) caspase-dependent PARP1 cleavage and (2) DNA damage-dependent apoptosis resulting from reduced full-length PARP1. The latter occurs through inhibition of METTL3-mediated m 6 A modification and subsequent suppression of PARP1 translation. Moreover, we found that RSL3 retains pro-apoptotic functions in PARPi-resistant cells and effectively inhibits PARPi-resistant xenograft tumor growth in vivo. Conclusions RSL3 orchestrates ferroptosis-apoptosis crosstalk via PARP1, demonstrating therapeutic potential against tumorigenesis, particularly in PARPi-resistant malignancies. Graphical
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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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PubMed
高影响因子
FASEB JOURNAL
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2025
·Vol. 39
·期 24
·e71369
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IF 4.2
Mengxin Li,Xuanzhong Wang,Jinghui Hong,Xin Guan,Yichang Chen,Hongxu zhou,Xin Wang,Baoling Liang,Xiaochuan Gao,Yuheng Wu,Dong Song
Breast cancer (BC) continues to be a representative malignancy globally, with its inherent heterogeneity and chemotherapy resistance posing significant therapeutic obstacles. Doxorubicin (Dox), a commonly utilized chemotherapeutic agent, is often constrained by dose-dependent toxicities and acquired resistance, which ultimately lead to suboptimal clinical outcomes in numerous BC patients. Co-treatment of Dox with RSL3, a small-molecule compound that inactivates glutathione peroxidase 4 (GPX4), was shown in this study to synergistically inhibit BC cell viability and proliferation at low doses in vitro and in vivo. In vitro tests showed that RSL3 exacerbated Dox-induced cell cycle arrest and apoptosis, markedly potentiating the cytotoxicity of Dox against BC cells. Mechanistically, RSL3 triggered ferroptosis-dependent ROS accumulation, leading to glycolytic impairment characterized by reduced intracellular ATP and pyruvate concentrations levels and downregulation of HKII, PFKP, and PKM2. Supplementation with exogenous sodium pyruvate ameliorated RSL3-induced glycolytic dysfunction, restored the changes in apoptosis-related protein expression caused by RSL3/Dox co-treatment, and reduced RSL3/Dox-induced cell apoptosis. Besides, according to in vivo studies, the combination of RSL3 and Dox further suppressed BC tumor growth without inducing significant adverse effects. On these accounts, RSL3 makes BC cells more sensitive to Dox by inducing glycolytic dysfunction, implying that RSL3/Dox co-treatment could be a viable therapeutic approach for BC patients. Graphical RSL3 Mitigates Doxorubicin Resistance in Breast Cancer via Targeted Disruption of Glycolytic Flux. Co-treatment with RSL3 and doxorubicin (Dox) synergistically inhibits breast cancer growth in vitro and in vivo. RSL3 sensitizes BC cells to Dox by inducing ferroptosis and ROS accumulation, which impairs glycolysis (reducing ATP/pyruvate and downregulating HK2/PFKP/PKM2). This metabolic disruption exacerbates Dox-induced cell cycle arrest and apoptosis. The combination therapy offers enhanced efficacy without significant toxicity, presenting a promising low-dose therapeutic strategy.
研究领域:
肿瘤学
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分子生物学
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癌症代谢
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药理学
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细胞生物学
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PubMed
高影响因子
iScience
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2022
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IF 6.107
Kun Fang,Sha Du,Dachuan Shen,Zhipeng Xiong,Ke Jiang,Dapeng Liang,Jianxin Wang,Huizhe Xu,Lulu Hu,Xingyue Zhai,Yuting Jiang,Zhiyu Xia,Chunrui Xie,Di Jin,Wei Cheng,Songshu Meng,Yifei Wang
Summary Ferroptosis is a new kind of regulated cell death that is characterized by highly iron-dependent lipid peroxidation. Cancer cells differ in their sensitivity to ferroptosis. Here we showed that the Suppressor of fused homolog (SUFU), a critical component in Hedgehog signaling, regulates ferroptosis sensitivity of breast cancer cells. Ectopic SUFU expression suppressed, whereas depletion of SUFU enhanced the sensitivity of breast cancer cells to RSL3-triggered ferroptosis through deregulation of ACSL4. Moreover, SUFU depletion promoted the activation of Yes-associated protein (YAP), thereby increasing the expression of ACSL4. Mechanistically, SUFU is associated with LATS1. Deletion of a region comprising residues 174–385 in SUFU disrupted SUFU binding to LATS1, thus abrogating SUFU-mediated downregulation of the YAP-ACSL4 axis and sensitivity to ferroptosis. Noteworthy, we showed that vincristine downregulated SUFU, thus increasing breast cancer cell sensitivity to RSL3 in vitro and in vivo . Together, our findings uncover SUFU as a novel regulator in ferroptosis sensitivity.
研究领域:
癌症生物学
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细胞信号传导
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分子生物学
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肿瘤学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2022
·Vol. 24
·期 1
·229
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IF 6.208
Mao Huang,Xinru Cao,Yucong Jiang,Yuehong Shi,Yazhen Ma,Dandan Hu,Xingju Song
Toxoplasma gondiiis a widespread intracellular pathogen that infects humans and a variety of animals. Dihydroartemisinin (DHA), an effective anti-malarial drug, has potential anti-T. gondiiactivity that induces ferroptosis in tumor cells, but the mechanism by which it killsT. gondiiis not fully understood. In this study, the mechanism of DHA inhibitingT. gondiigrowth and its possible drug combinations are described. DHA potently inhibitedT. gondiiwith a half-maximal effective concentration (EC50) of 0.22 μM. DHA significantly increased the ROS level of parasites and decreased the mitochondrial membrane potential, which could be reversed by ferroptosis inhibitors (DFO). Moreover, the ferroptosis inducer RSL3 inhibitedT. gondiiwith an EC50of 0.75 μM. In addition, RSL3 enhanced the DHA-induced ROS level, and the combination of DHA and RSL3 significantly increased the anti-Toxoplasmaeffect as compared to DHA alone. In summary, we found that DHA-induced ROS accumulation in tachyzoites may be an important cause ofT. gondiigrowth inhibition. Furthermore, we found that the combination of DHA and RSL3 may be an alternative to toxoplasmosis. These results will provide a new strategy for anti-Toxoplasmadrug screening and clinical medication guidance.Keywords:Toxoplasma gondii;dihydroartemisinin;ferroptosis inducer RSL3;mitochondrial membrane potential;ROS
研究领域:
寄生虫学
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药理学
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传染病学
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PubMed
高影响因子
Phytochemistry Letters
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2023
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IF 1.7
Yu-Chen Chen,Qiong Zheng,Hui Lu,Yi-Xin Zhuang,Ting-Ting Gong,Lie-Feng Ma,Zha-Jun Zhan
A new flavonoid glycoside bearing an unusual furan ring, epimedokoreanin F ( 1 ), was isolated from Epimedium brevicornu , along with 17 known flavonoids ( 2−18 ). The structures of these flavonoids were identified based on interpretation of spectroscopic data and comparison with literature data. Biologically, compounds 1−4 exhibited significant neuroprotective effects on the model of RSL3-induced ferroptosis in HT22 cells. Among them, compound 1 displayed the best activity with EC 50 values of 0.95 μ M, and can be used as lead compound for the development of neuroprotective agent to treat neurological diseases .
研究领域:
药理学
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神经科学
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生物化学
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植物化学
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高影响因子
Biomolecules
·
2025
·Vol. 15
·期 12
·1749
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IF 4.8
Lingyan Chen,Dejian Chen,Fengzhuo Yang,Xinyi Chen,Binjiao Zheng
Background: Breast cancer remains the most common malignancy among women worldwide. Current systemic treatment strategies include chemotherapy, immunotherapy, bone-stabilizing agents, endocrine therapy for hormone receptor-positive disease, anti-HER2 therapy for HER2-positive disease, and poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA mutation cases. However, effectively overcoming drug resistance and reducing recurrence and metastasis rates remain major therapeutic challenges. Methods: To investigate the underlying mechanism of RSL3 in PARPi-resistant breast cancer cells, we treated several PARPi-resistant breast cancer cells with varying doses of RSL3. The regulatory proteins of STAT3 were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Immunoprecipitation and ubiquitination assay were performed to identify the STAT3 ubiquitination levels. Results: Recently, we identified that RSL3, a ferroptosis activator, exhibits potent antitumor activity against PARPi-resistant breast cancer. Yet, its underlying mechanism remains unclear. Here, we demonstrate that RSL3 directly targets STAT3 and promotes its degradation via the ubiquitination pathway, leading to increased LC3-II levels and decreased p62 expression. These changes ultimately enhance autophagy, which at least partially contributes to elevated apoptosis. Rescue experiments confirmed that STAT3 overexpression reverses RSL3-induced autophagy and apoptosis. Conclusions: Our findings highlight RSL3 as a promising therapeutic agent and STAT3 as a potential target for treating PARPi-resistant breast cancer.
研究领域:
肿瘤学
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分子生物学
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癌症治疗学
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细胞信号传导
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PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
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IF 6.3
Li Li,Wenqian Cai,Hao Zhang,Jiuren Tang,Yongjie Yang,Yang Huang,Qing Xi,Rongxin Zhang
Renal fibrosis is the most common pathway for the development of end-stage renal disease (ESRD) in various kidney diseases. Currently, the treatment options for renal fibrosis are limited. Ferroptosis is iron-mediated lipid peroxidation, triggered mainly by iron deposition and ROS generation. Notably, the kidney is the most sensitive of all tissues to iron-dependent ferroptosis, and the inhibition of ferroptosis is an effective therapeutic strategy for the treatment of kidney fibrosis. Nonetheless, the pathways involved in ferroptosis in renal fibrosis are still unclear. Bergapten, a natural coumarin derivative, is mainly found in bergapten essential oil, grapefruit juice, and other commonly used plants, and it has various pharmacological effects. However, the role that ferroptosis plays in renal fibrosis and the potential therapeutic benefits of bergapten remain unclear. In this study, we investigated the therapeutic effects of bergapten on renal fibrosis and its mechanisms. We investigated the anti-fibrotic effects of bergapten in in vivo and in vitro models of renal fibrosis. Initially, network pharmacological analysis was employed to predict the potential therapeutic impact of bergapten on renal fibrosis. We then explored the potential therapeutic role of bergapten in obstructive nephropathy, which is due to unilateral ureteral obstruction (UUO). Furthermore, RNA-Seq was conducted to investigate the possible mechanism of bergapten against renal fibrosis. Additionally, Bergapten demonstrated a significant improvement in TGF-β1-induced fibrosis and RSL3-induced renal tubular epithelial cell ferroptosis; these findings are consistent with those of the in vivo studies. Our findings indicate that bergapten is a potential treatment for renal fibrosis. Treatment with bergapten significantly reduced the expression of fibronectin and α-SMA in the damaged kidneys of UUO mice, thereby improving fibrosis. Meanwhile, bergapten protected against fibrosis caused by TGF-β1 and ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibitor RSL3. Significantly, bergapten therapy alleviated renal fibrosis by modulating ferroptosis. We found that bergapten inhibited PI3K phosphorylation and indirectly restored GPX4 expression. In conclusion, we have revealed the nephroprotective effect of bergapten, whose mechanism of action is related to the inhibition of ferroptosis, and it is expected that it will be developed as a therapeutic agent for the treatment of renal fibrosis. This study aims to explore the effect of bergapten on renal fibrosis ferroptosis. Collectively, these results demonstrate that bergapten is an inhibitor of ferroptosis and provides a new treatment strategy for diseases associated with ferroptosis.
研究领域:
肾病学
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药理学
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分子生物学
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PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
·
2023
·Vol. 18
·期 1
·1-15
·
IF 2.6
Xue Xiang,Dai Tianming,Chen Junyan,Xu Yangyang,Yang Zhenyu,Huang Jian,Xu Wuyan,Li Siming,Meng Qingqi
Background Osteoarthritis (OA) is a prevalent disease plaguing the elderly. Recently, chondrocyte ferroptosis has been demonstrated to promote the progression of OA. Peroxisome proliferator-activated receptor-γ (PPARγ) is an important factor in maintaining cartilage health. However, the relationship between PPARγ and chondrocyte ferroptosis in OA and its mechanism is completely unclear.Methods We established a surgically induced knee OA rat model to investigate PPARγ and chondrocyte ferroptosis in OA. Rat knee specimens were collected for Safranin O/Fast Green staining and immunohistochemical staining after administered orally placebo or pioglitazone (PPARγ agonist) for 4 weeks. We used RSL3 to establish a chondrocyte ferroptosis model cultured in vitro to study the role of PPARγ activation toward ferroptosis, mitochondrial function, and PTEN-induced putative kinase 1 (Pink1)/Parkin-dependent mitophagy. GW9662 (PPARγ antagonist), Mdivi-1 (mitophagy inhibitor), and chloroquine (mitophagy inhibitor) were employed to investigate the mechanism of PPARγ-Pink1/Parkin-dependent mitophagy in the inhibition of ferroptosis.Results We found that PPARγ activation by pioglitazone attenuated not only OA but also inhibited the expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 (ACSL4) at the same time in rats. Furthermore, in vivo and in vitro data indicated that PPARγ activation restored Pink1/Parkin-dependent mitophagy, improved mitochondrial function, inhibited chondrocyte ferroptosis, and delayed the progression of OA.Conclusion sThe present study demonstrated that PPARγ activation attenuates OA by inhibiting chondrocyte ferroptosis, and this chondroprotective effect was achieved by promoting the Pink1/Parkin-dependent mitophagy pathway.
研究领域:
骨科
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细胞生物学
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药理学
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PubMed
高影响因子
Research
·
2025
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IF 10.7
Chengjunyu Zhang,Sen Liu,Jianhui Zhang,Junlin Lu,Zehua Chen,Bolin Pan,Chu Liu,Ming Huang,Hengji Zhan,Hongjin Wang,Siting Chen,Kaiwen Jie,Baoqing He,Jingdie Wu,Ye Li,Haifeng Wang,Jing Zhao,Qiang Zhang,Xu Chen
Ferroptosis has promising potential for augmenting antitumor effects, but monotherapy with ferroptosis inducers in vivo has been reported to have limited efficacy in tumor management. The development of synergistic strategies with targeted capabilities is crucial for enhancing the antitumor efficacy of ferroptosis inducers. In this study, we designed and characterized a novel self-assembled nanomedicine by mixing ferrous ions (Fe 2+ ) and epigallocatechin gallate (EGCG) in a controllable manner and encapsulating the ferroptosis inducer RSL3, named Fe-EGCG@RSL3. This multifunctional nanomedicine effectively induces ferroptosis and growth inhibition in bladder cancer cells and patient-derived organoids. In vivo, Fe-EGCG@RSL3 was enriched in the subcutaneous tumors of allogenic and xenograft mouse models, thereby substantially overcoming RSL3 resistance. Intravesical instillation of Fe-EGCG@RSL3 controls orthotopic bladder tumor progression. Furthermore, nanomedicine potentiates the therapeutic effect of anti-programmed cell death protein 1 (PD1) immunotherapy by increasing the cytotoxicity of CD8 + T cells to cancer cells and modulating the proportions of both T-cell and myeloid cell subpopulations within the tumor immune microenvironment. Overall, Fe-EGCG@RSL3 has dual functions as a multifaceted nanomedicine that integrates ferroptosis induction with immunomodulation, offering a novel and clinically translatable strategy for bladder cancer therapy.
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高影响因子
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