JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Congcong Lin,Jiamin Sun,Yun Yang,Xinyao Pan,Shiyu Wang,Xiaoyang Li,Yan Zhang,Huile Gao,Chunli Gan
The development of chemotherapy resistance poses a major challenge in cancer therapy. Ferroptosis, a unique type of cell death, offers a promising strategy to combat this resistance. Herein, a peptide-based nanoassembly (PTX@CPG) consisting of paclitaxel (PTX), chlorin e6 (Ce6), and FFVLKPLGLAGK-(PEG8) 3 was constructed to promote ferroptosis through reactive oxygen species (ROS) accumulation and overcome chemoresistance. Specifically, the small-sized PTX@CPG nanoparticles effectively penetrate tumors, where the microenvironment-responsive peptide is selectively cleaved by the high expression of matrix metalloproteinase 2. This process facilitates the targeted release of PTX and its reassembly into nanofibers, improving the tumor retention of Ce6 and enhancing its cellular uptake. The synergistic therapeutic effects of PTX in combination with photodynamic therapy on triple-negative breast cancer cells were validated through both in vitro and in vivo experiments. Impressively, upon laser irradiation, PTX@CPG significantly increased ROS production, thereby amplifying the ferroptosis-inducing effects of PTX. Moreover, ferroptosis triggered by PTX@CPG with laser reduced the levels of P-glycoprotein and glutathione peroxidase 4, contributing to the alleviation of chemoresistance. Overall, PTX@CPG with laser demonstrated effective spatial targeting and drug retention, enhancing ferroptosis through ROS accumulation and showcasing a promising approach for overcoming chemotherapy resistance in cancer therapy.
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Cell Death Discovery
·
2025
·Vol. 11
·期 1
·1-17
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IF 7
Wei Guojiang,Huang Ying,Li Wenya,Xie Yuxin,Zhang Deyi,Niu Yuanjie,Zhao Yang
Metabolic reprogramming in prostate cancer has been widely recognized as a promoter of tumor progression and treatment resistance. This study investigated its association with ferroptosis resistance in prostate cancer and explored its therapeutic potential. In this study, we identified differences in the epithelial characteristics between normal prostate tissue and tissues of various types of prostate cancer using single-cell sequencing. Through transcription factor regulatory network analysis, we focused on the candidate transcription factor, SREBF1. We identified the differences in SREBF1 transcriptional activity and its association with ferroptosis, and further verified this association using hdWGCNA. We constructed a risk score based on SREBF1 target genes associated with the biochemical recurrence of prostate cancer by combining bulk RNA analysis. Finally, we verified the effects of the SREBPs inhibitor Betulin on the treatment of prostate cancer and its chemosensitization effect. We observed characteristic differences in fatty acid and cholesterol metabolism between normal prostate tissue and prostate cancer tissue, identifying high transcriptional activity of SREBF1 in prostate cancer tissue. This indicates that SREBF1 is crucial for the metabolic reprogramming of prostate cancer, and that its mediated metabolic changes promoted ferroptosis resistance in prostate cancer in multiple ways. SREBF1 target genes are associated with biochemical recurrence of prostate cancer. Finally, our experiments verified that SREBF1 inhibitors can significantly promote an increase in ROS, the decrease in GSH, and the decrease in mitochondrial membrane potential in prostate cancer cells and confirmed their chemosensitization effect in vivo. Our findings highlighted a close association between SREBF1 and ferroptosis resistance in prostate cancer. SREBF1 significantly influences metabolic reprogramming in prostate cancer cells, leading to ferroptosis resistance. Importantly, our results demonstrated that SREBF1 inhibitors can significantly enhance the therapeutic effect and chemosensitization of prostate cancer, suggesting a promising therapeutic potential for the treatment of prostate cancer.
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ACS Applied Materials & Interfaces
·
2021
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IF 9.229
Yabing Zhang,Xiangyi Ren,Yan Wang,Dongxu Chen,Ling Jiang,Xi Li,Tao Li,Minfeng Huo,Qian Li
Ferroptosis is a new form of regulated cell death depending on elevated iron (Fe2+) and lipid peroxidation levels. Myocardial ischemia/reperfusion (I/R) injury has been shown to be closely associated with ferroptosis. Therefore, antiferroptosis agents are considered to be a new strategy for managing myocardial I/R injury. Here, we developed polydopamine nanoparticles (PDA NPs) as a new type of ferroptosis inhibitor for cardioprotection. The PDA NPs features intriguing properties in inhibiting Fe2+ accumulation and restoring mitochondrial functions in H9c2 cells. Subsequently, we demonstrated that administration of PDA NPs effectively reduced Fe2+ deposition and lipid peroxidation in a myocardial I/R injury mouse model. In addition, the myocardial I/R injury in mice was alleviated by PDA NPs treatment, as demonstrated by reduced infarct size and improved cardiac functions. The present work indicates the therapeutic effects of PDA NPs against myocardial I/R injury via preventing ferroptosis.
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Food & Function
·
2021
·Vol. 12
·期 24
·12671-12682
·
IF 5.396
Jing-yi Ren,Bo-wen Yin,Xiang Li,Si-qi Zhu,Jin-liang Deng,Yi-ting Sun,Zhen-ao Zhang,Zi-hao Guo,Huan-ting Pei,Fan Zhang,Rui-qiang Li,Feng-ge Chen,Yu-xia Ma
Objective: This study aimed to elucidate the pharmacological effects of sesamin (Ses) and its mechanism of action towards PM2.5-induced cardiovascular injuries. Method: Forty Sprague Dawley (SD) rats were randomly divided into five groups: a saline control group; a PM2.5 exposure group; and low-, middle-, and high-dose Ses pretreatment groups. The SD rats were pretreated with different concentrations of Ses for 21 days. Afterward, the rats were exposed to ambient PM2.5 by intratracheal instillation every other day for a total of three times. The levels of inflammatory markers, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6), and indicators related to oxidative responses, such as total superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA), were measured in the blood and heart. The expression of ferroptosis-related proteins in heart tissues was determined via western blot and immunohistochemistry. Results: Ses pretreatment substantially ameliorated cardiovascular injuries in rats as evidenced by the decrease in the pathological score and collagen area. The decreased levels of SOD, GSH, and GSH-Px in the heart and serum were inhibited by Ses. In addition, Ses not only notably increased the activity of antioxidant enzymes but also reduced the levels of MDA, CK, LDH, CK-MB, IL-6, TNF-α, IL-1β, and IL-6. Furthermore, Ses pretreatment upregulated the expression levels of GPX4, SLC7A11, TFRC, and FPN1 and inhibited the expression levels of FTH1 and FTL. Conclusion: Ses pretreatment could ameliorate PM2.5-induced cardiovascular injuries perhaps by inhibiting ferroptosis. Therefore, Ses pretreatment may be a novel strategy for the prevention and treatment of PM2.5-induced cardiovascular injury.
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Journal of Materials Chemistry B
·
2025
·
IF 5.7
Lanfu Zheng,Wei Jiang,Shuming Tian,Zepeng Feng,Yanan Qi,Hongyang Fu,Liting Qi,Lianrui Chen
Photothermal therapy (PTT) represents a non-invasive therapeutic modality with considerable potential for tumor ablation. However, the complex tumor microenvironment (TME) presents substantial challenges to conventional PTT monotherapy. In this study, we developed a nanomedicine (Fe 3 O 4 @GOx@PDA) designed to synergistically eradicate tumor cells by integrating PTT with starvation therapy and ferroptosis induction. Glucose oxidase (GOx) catalyzes the oxidation of intratumoral glucose to gluconic acid and hydrogen peroxide (H 2 O 2 ). Simultaneously, the resultant H 2 O 2 facilitates intracellular Fenton-like reactions, generating reactive oxygen species (ROS) that trigger lipid peroxidation. Furthermore, Fe 2+ ions liberated within the TME react with H 2 O 2 via a Fenton-like reaction to produce abundant ROS. This ROS surge stimulates macrophage polarization towards the M1 phenotype, thereby further suppressing the proliferation and metastatic potential of colorectal cancer (CRC) cells. This multimodal therapeutic strategy, leveraging Fe 3 O 4 @GOx@PDA, demonstrates potent synergistic antitumor efficacy coupled with favorable biosafety, presenting a promising therapeutic approach for clinical colorectal cancer management.
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JOURNAL OF LIPID RESEARCH
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2025
·
IF 4.1
Shaojun Pei,Wen Wang,Tingze Feng,Qiuping Wang,Yuhan Wang,Hong-Xu Liu,Xinmiao Liang,Hai-long Piao
S -palmitoylation is a dynamic and reversible post-translational modification that plays crucial roles in cancer progression. Here, we found the oncogene of metadherin (MTDH) modulates lipid metabolism and ferroptosis by its S -palmitoylation. We demonstrate that MTDH is S -palmitoylated at Cys-75 in the endoplasmic reticulum by ZDHHC1/9 and S -depalmitoylated by APT1. The flexible loop and the α-helix length in the MTDH N-terminus affect its S -palmitoylation level. In addition, metabolomics analysis found that the S -palmitoylated MTDH increases intracellular levels of triglycerides, phosphatidylethanolamines, and phosphatidylcholines. However, the non- S -palmitoylation form of MTDH-CS enhanced the interaction of between MTDH and the ferroptosis enhancer of Acyl-CoA synthetase long-chain family member 4 (ACSL4), thereby reducing ferroptosis sensitivity in breast cancer cell. Taken together, targeting MTDH S -palmitoylation may represent a novel strategy for breast cancer therapy.
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REDOX REPORT
·
2025
·
IF 7.4
Jingyi Ren,Ziyi Wang,Yadong Zhang,Huanting Pei,Rui Wen,Zhenao Zhang,Siqi Zhu,Xiaoya Sun,Bowen Yin,Shenghe Li,Yuxia Ma
Background: Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure. Sesamin (Ses), a natural polyphenolic compound, possesses diverse pharmacological properties. This study was to explore the effects of Ses on APAP-induced liver injury and the underlying molecular mechanism.Methods: In vivo, C57BL/6J mice were treated with different doses of Ses for 28 days. After overnight food deprivation, mice were intraperitoneally injected with a single dose of APAP. In vitro, the AML12 and HepG2 cells were pre-treated with Ses and then treated with APAP.Results: Ses dramatically alleviated APAP-induced hepatocellular injury in vitro and in vivo. Proteomic analysis suggested that the differentially expressed proteins were enriched in ferroptosis, autophagy, and FoxO signaling pathways between the APAP group and the Ses-treated groups. We subsequently found that ferroptosis was significantly inhibited, and autophagy was significantly enhanced in the Ses-treated group. Consistently, Ses obviously reduced the expression of Foxo1. However, hepatocyte-specific knockout Foxo1 abolished the effect of Ses on hepatocyte autophagy and ferroptosis caused by APAP in mice.Conclusions: Our findings demonstrate that Ses attenuates APAP-induced hepatotoxicity through Foxo1, which mediates both the activation of autophagy and the inhibition of ferroptosis. It provides a new strategy for the prevention and treatment of drug-induced liver injury.
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Biomaterials Advances
·
2024
·
IF 5.5
Yang Liu,Pengyuan Qi,Gaojie Chen,Zhiquan Lang,Jike Wang,Xinghuan Wang
Immunotherapy is a promising mainstream approach in anti-tumor therapy. It boasts advantages such as durable responses and lower side effects. However, there are still some limitations to be addressed. Current cancer immunotherapy has shown low response rates due to inadequate immunogenicity of certain tumor cells. To address these challenges, an acid-specific nanoreactor was developed, designed to induce immunogenicity by triggering ferroptosis in tumor cells. The nanoreactor integrates glucose oxidase (GOx) with a single-atom nanoenzyme (SAE), which exhibits high peroxidase (POD)-like activity in the acidic tumor microenvironment (TME). This specific acid-sensitivity transforms endogenous hydrogen peroxide (H 2 O 2 ) into cytotoxic hydroxyl radicals (•OH). GOx enhances the POD-like SAE activity in the nanoreactor by metabolizing glucose in tumor cells, producing gluconic acid and H 2 O 2 . This nanoreactor induces high levels of oxidative stress within tumor cells through the synergistic action of SAE and GOx, leading to depletion of GSH and subsequently triggering ferroptosis. The resulting nanoreactor-induced ferroptosis leads to immunogenic cell death (ICD) and significantly recruits T lymphocyte infiltration in tumor tissues. This study was designed with the concept of triggering ferroptosis-dependent ICD mechanism in bladder cancer cells, and developed an acid-specific nanoreactor to enhance the immunotherapy efficacy for bladder cancer, which introduces a novel approach for immunotherapy of bladder cancer.
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Materials Today Bio
·
2026
·
IF 11
Zheng Peng,Xiao-Jian Li,Yu-Long Xi,Xiao-Long Zhu,Yue Lu,Yan Zhou,Hui-Ying Yan,Juan Wang,Zheng-Mao Yang,Chun-Hua Hang,Yi-Nan Ding,Jing-Lin Wang,Wei Li
Subarachnoid hemorrhage (SAH) is a type of stroke mainly caused by the bursting of brain aneurysms, releasing iron ions into the subarachnoid space and subsequently inducing ferroptosis. Despite the utilization of various ferroptosis-inhibiting pharmacological agents to enhance neurological outcomes post-SAH, challenges such as inadequate targeting and suboptimal drug utilization persist. In response to these limitations, we have developed a novel spatiotemporal cascade reaction liposome that recombinant proteins incorporating neuron-targeting peptides and the functional structural domain of ferroptosis suppressor protein 1 (FSP1) were immobilized on the external surface of liposomes, which were internally loaded with coenzyme Q10 (CoQ10) to construct FSP1-Lipo-CoQ10.The purpose of this study is to investigate the neuroprotective effects of FSP1-Lipo-CoQ10 following SAH. As a result, FSP1-loaded liposomes enable targeted delivery to neurons in the lesion area and increase FSP1 levels on the cell membrane. Among the three liposomal formulations, FSP1-Lipo-CoQ10 demonstrated the most potent anti-ferroptosis effects and the greatest improvement in neurological function. FSP1-Lipo-CoQ10 provides a new approach for the therapeutic management of ferroptosis post-SAH and ameliorates associated pathological conditions.
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Wupei Pan,Xiaoyi Zou,Wenxin Tang,Xin Zheng,Minjuan Xie,Jie Zhou
Sodium aescinate (SA), derived from seeds of the Chinese herb Suoluozi ( Aesculus wilsonii Rehd.), has been linked to severe kidney injury during clinical use. We previously found that SA induces nephrocyte ferroptosis, and upregulation of glutathione peroxidase 4 (GPX4) or ferroptosis suppressor protein 1 (FSP1) expression only partially attenuates this toxic effect. In this study, we demonstrated that SA reduced cellular levels of hydrogen sulfide (H 2 S) and reduced coenzyme Q10 (CoQ10H 2 ), leading to impaired antioxidant defense and lipid peroxidation (LPO) in renal cells. Mechanistically, SA suppressed the expression of activating transcription factor 4 (ATF4), cystathionine γ-lyase (CTH) and sulfide: quinone oxidoreductase (SQOR). The SA-induced downregulation of CTH expression was attributed to the decreased recruitment of ATF4 to the cis -regulatory element (CRE) of the CTH promoter. ATF4 overexpression in SA-treated cells upregulated CTH expression, which elevated H 2 S and CoQ10H 2 levels, improved antioxidant defense, and reduced ferroptosis. Critically, CTH silencing completely abrogated these protective effects. Conversely, CTH or SQOR overexpression, or H 2 S supplementation restored CoQ10H 2 levels and protected against SA-induced ferroptosis. However, in SQOR-deficient cells, neither intervention rescued CoQ10H 2 nor alleviated nephrotoxicity despite increased H 2 S levels. Additionally, alternative oxidase (AOX) overexpression abolished the protective effect of the ATF4/CTH/SQOR axis by oxidizing CoQ10H 2 back to its inactive form. In conclusion, SA induced ferroptosis-mediated kidney injury by disrupting the ATF4/CTH/SQOR axis, leading to reduced CoQ10H 2 levels and impaired redox homeostasis. This study introduces this pathway as a novel therapeutic target for SA-induced nephrotoxicity.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 5.7
Zi-Kun Lin,Cheng Chen,Jia-Hui Hong,Ping Tan,Yao Yuan,Peng Wang,Xue-Sen Yang,Ya Liu,Hai-Gang Zhang
Heat stroke (HS) represents a severe public concern due to its high mortality rate, with cardiac injury recognized as a critical pathological process. Schisandra chinensis has been utilized in traditional Chinese prescription to prevent and treat heat stroke, but the underlying mechanism is unclear. The present study was designed to explore the cardioprotective effect of its main component, Schisandrin B (SchB). We analyzed cardiac RNA sequencing differentially expressed genes (DEGs) between HS and control mice to initially evaluate SchB's potential in attenuating HS-induced cardiac injury and its relation with ferroptosis. Using murine (core temperature reaching 42 °C) and cellular HS models (42 °C exposure for 5 h), we verified the cardiac preventive effects of SchB against HS-induced injury and its role in the modifying of ferroptosis. Bioinformatic analysis suggested SchB could modulate ferroptosis during HS. SchB pretreatment significantly prolonged time to reach HS in mice, alleviated cardiomyocyte injury, decreased Fe 2+ and malondialdehyde (MDA) levels while elevated glutathione (GSH) levels. Additionally, SchB downregulated acyl-CoA synthetase long chain family member 4 (ACSL4) expression and upregulated solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) in both murine and H9c2 cells HS models. Concurrently, SchB upregulated sirtuin 1 (SIRT1) expression while inhibiting the nuclear translocation of high mobility group box 1 (HMGB1). These findings suggest that SchB pretreatment may attenuate HS-induced cardiac ferroptosis and the associated myocardial injury through modulation of the SIRT1/HMGB1/ACSL4 pathway.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2026
·
IF 9.6
Yong Huang,Tao Quan,Bowen Li,Chaohui Zhen,Haiqian Zhang,Zhiyao Li,Chongzhi Wu,Rui Liang,Lihe Sun,Xin Xie
Triple-negative breast cancer (TNBC), lacking effective therapeutic targets, is highly aggressive, prone to metastasis, and associated with poor prognosis, highlighting the necessity for innovative therapeutic strategies. Ferroptosis, an emerging form of iron-dependent programmed cell death, presents a promising treatment approach. However, its effectiveness is often hindered by adaptive resistance within the tumor microenvironment and inefficient drug delivery. To address these limitations, the glutathione (GSH)-responsive disulfide linker (-SS-) was utilized to engineer rhein (Rhe, chemotherapeutic agent) and ferrocene (Fc, ferroptosis booster) into the self-assembling small-molecule prodrug RSSF. Sorafenib (SOR), a ferroptosis inducer, was stably loaded into RSSF via a simple nanoprecipitation method, yielding the newly nanoprodrug designated as SOR@RSSF nanoparticles (NPs) for the combination therapy of TNBC. SOR@RSSF NPs exhibit markedly enhanced cellular uptake and enable the highly specific and synchronous release of Rhe, Fc, and SOR in response to intracellular GSH levels. Notably, Fc efficiently generates hydroxyl radicals (•OH) through the Fenton reaction, thereby inducing pronounced oxidative stress, while SOR concurrently impaired the cellular ferroptosis defense machinery. Combined with the chemotherapeutic activity of Rhe, the resulting lipid peroxide (LPO) accumulation and GSH depletion synergistically trigger both ferroptosis and apoptosis selectively in tumor cells. In a 4T1 tumor-bearing mouse model, SOR@RSSF NPs significantly inhibited tumor progression while maintaining a favorable biosafety profile. Overall, this study presents a promising ferroptosis-sensitizing strategy using a nanoprodrug delivery system for combination therapy against TNBC.
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