INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Nannan Xu,Wenyi Fu,Jiake Wu,Shuai Zhao,Chunyang Tian
Rheumatoid arthritis (RA) is one of the most common chronic inflammatory autoimmune diseases, and ferroptosis has been associated with its pathogenesis. TRIM16 belongs to the TRIM protein family and possesses various biological function. However, the role of TRIM16 in RA has not been reported. Our results showed that TRIM16 was upregulated in collagen-induced arthritis (CIA) mice, and TRIM16 overexpression alleviated joint inflammation. Notably, the level of 4-HNE was decreased in CIA mice, whereas TRIM16 overexpression restored it. The expression of GPX4 and SLC7A11 was upregulated in CIA mice, whereas TRIM16 overexpression significantly suppressed their levels, suggesting that TRIM16 promotes ferroptosis. We then detected TRIM16 expression in TNF-α-induced fibroblast-like synoviocytes (FLS), and found that TNF-α stimulation reduced TRIM16 expression. Overexpression of TRIM16 increased the lipid ROS, Fe 2+ levels, and LDH activity, while reducing GSH-PX and GSH activities. Moreover, TNF-α treatment increased GPX4 and SLC7A11 expression but decreased ACSL4 levels, and TRIM16 overexpression reversed these effects. TRIM16 knockdown reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Furthermore, Fer-1 treatment reduced lipid ROS levels and increased GPX4 and SLC7A11 expression. Mechanistically, TRIM16 directly binds to Snai1, promoted its K48-linked ubiquitination, and specifically ubiquitinates Snai1 at the K146 site. Overexpression of Snai1 decreased the lipid ROS levels and increased the GSH content. Our study identifies TRIM16 as a promoter of ferroptosis in TNF-α-induced FLS by enhancing Snai1 ubiquitination and degradation. In summary, our study presented that TRIM16 plays a protective role in RA.
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高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Ziqi Shen,Yueru Pang,Ruixin Kang,Xiawei Zhou,Chao Li,Siyuan Yu,Lin Luo,Feiyang Liu,Jun Zhang,Qi Shen
Fusobacterium nucleatum ( Fn. ) can colonize breast cancer tissue to promote tumor progression by inducing immunosuppression. Targeted therapeutic strategies against intratumoral bacteria remain unexplored and have potential in tumor immunotherapy. Here, a novel biomimetic nanoparticle (FMV@PCFPC) is developed for intratumoral immunosuppressive bacteria clearance and tumor immunogenic cell death (ICD) activation by inducing dual ferroptosis in intratumoral bacteria and tumors. A host-guest complex of hemirotaxane (mPEG-β-CD/α-CD) and polyethyleneimine-ferrocene (Fc-PEI) is constructed, designated as PCFP. PCFP is loaded with antibacterial drug cinnamaldehyde (CA) and wrapped with Fn. -secreted vesicles (FMVs) to form the system FMV@PCFPC. FMVs assist PCFPC in targeting tumors to promote ferrocene and cinnamaldehyde uptake. Fe 2+ in ferrocene, together with glutathione (GSH) -consuming cinnamaldehyde, induces ferroptosis in intratumoral bacteria to relieve tumor immunosuppression. Similarly, PCFPC induces tumor ferroptosis to activate ICD, therefore enhancing antigen presentation and DC maturation. ICD activation works synergistically with intratumoral bacteria clearance to promote cytotoxic T lymphocytes (CTL) activation, inducing robust tumor destruction. Furthermore, killed Fn. bacterial fragments and pathogen-associated molecular patterns (PAMPs) on FMVs function as immunologic adjuvants to further boost immune response. This strategy of intratumoral bacterial clearance and tumor ICD activation relies on dual ferroptosis to effectively enhance anti-tumor immunity, showing great potential in breast cancer treatment.
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CELL DEATH AND DIFFERENTIATION
·
2025
·
IF 15.4
Chen Zixiang,Niu Kaifeng,Li Mengge,Deng Yuchun,Zhang Ji,Wei Di,Wang Jiaqi,Zhao Yongliang
Tumor cells evolve strong antioxidant capacities to counteract the abnormal high level of reactive oxygen species (ROS) in the tumor microenvironment. Glutamate-cysteine ligase catalyzing subunit (GCLC) for synthesis of antioxidant glutathione (GSH) represents the key enzyme to maintain redox homeostasis of tumor cells, however, whether its activity is regulated by posttranslational modifications, such as succinylation, remains to be clarified. Here, we demonstrate the existence of succinylation modification on GCLC by in vitro and in vivo assays. NAD-dependent deacetylase Sirtuin-2 (SIRT2) serves as the desuccinylase and catalyzes GCLC desuccinylation at sites of K38, K126, and K326. Specifically, GCLC directly interacts with SIRT2, which can be substantially enhanced upon ROS treatment. This strengthened association results in GCLC desuccinylation and activation, consequently promoting GSH synthesis and rendering cancer cells resistant to ferroptosis induction. Depletion of SIRT2 decreases total GSH level and meanwhile increases the cellular susceptibility to ferroptosis, which can mostly be rescued by introducing wild-type GCLC, but not its 3K-E mutant. We further demonstrated that histone acetyltransferase P300 serves as the succinyltransferase of GCLC, and their association is remarkably decreased after ROS treatment. Thus, SIRT2-regulated GCLC succinylation represents an essential signaling axis for cancer cells to maintain their redox balance in coping with oxidative stress-induced ferroptosis.
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PHYTOMEDICINE
·
2025
·
IF 8.3
Yu Liu,Honglin Chen,Kun Chen,Qi Shang,Feng Lin,Peng Zhang,You Zhang,Weicheng Qin,Huiwen Liu,Weiyu Qiu,Xingda Chen,Yan Gong,Yixuan Jiang,Yuzhuo Zhang,Jiahui He,Wenhua Zhao,Hui Ren,Gengyang Shen,Xiaobing Jiang
Background Skeletal muscle atrophy, which is a debilitating condition exacerbated by estrogen deficiency, lacks effective therapeutic interventions. Although ferroptosis (an iron-dependent form of cell death driven by lipid peroxidation) has emerged as a contributor to muscle degeneration, its regulatory mechanisms remain poorly defined. In this study, we identified luteolin, which is a natural flavonoid, as a potent inhibitor of ferroptosis that mitigates estrogen deficiency-induced muscle atrophy by targeting SLC7A11. Purpose The aim of this study was to investigate the role of ferroptosis in the anti-muscle atrophy effects of luteolin. Methods Via database screening, luteolin was identified as a potential drug for improving muscle atrophy, and the promotion of C2C12 myogenic differentiation by luteolin was detected by using immunofluorescence (IF), quantitative reverse transcription PCR (RT-qPCR) and western blot (WB). The mechanism of luteolin-mediated ferroptosis in muscle atrophy was confirmed by RNA-seq, transmission electron microscopy (TEM), and GSH, MDA, SOD and Fe 2+ assays. Molecular docking, molecular dynamics simulation, surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and siRNA-mediated gene knockout were applied to validate the notion that the mechanism of luteolin treatment of muscle atrophy involves target binding to SLC7A11. In addition, this study confirmed the role of luteolin in ameliorating muscle atrophy via the modulation of the SLC7A11-mediated ferroptosis pathway in vivo . Finally, the effect of luteolin on the myogenic differentiation of HsKMCs was investigated. Results Luteolin promotes myogenic differentiation and significantly inhibits myotube atrophy, with the main mechanism of these effects involving the direct binding of luteolin to the SLC7A11 protein to inhibit the occurrence of ferroptosis. We confirmed that luteolin can inhibit ferroptosis in muscle tissue and improve the loss of muscle mass and strength due to muscle atrophy in vivo . In addition, luteolin significantly inhibited myotube atrophy in HsKMCs and promoted their myogenic differentiation by modulating the SLC7A11-mediated ferroptosis. Conclusions Our findings demonstrate that luteolin regulates myogenesis and prevents muscle atrophy through binding to SLC7A11 and subsequently inhibiting ferroptosis. This study elucidates the critical role of the SLC7A11-ferroptosis axis in preserving muscle physiology during atrophy, while identifying luteolin as a therapeutic agent capable of targeting SLC7A11 to suppress ferroptosis and alleviate muscle atrophy.
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高影响因子
APPLIED ORGANOMETALLIC CHEMISTRY
·
2025
·Vol. 39
·期 5
·e70143
·
IF 0
Lu Hong,Qiaoyu Chen,Lei Rao,Zhen Wang,Bing Wang,Qing He,Wenxin Lin
Generally, single cancer treatment is insufficient to achieve ideal therapeutic effect. Multimodal therapy has the potential to overcome efficacy challenges and reveals great promise in enhancing therapeutic effect. Herein, a combination treatment system (DOX@Fe-PBC) based on chemotherapy, chemodynamic therapy (CDT), and ferroptosis was constructed by loading anticancer drug doxorubicin hydrochloride (DOX) into Fe-based metal–organic framework (Fe-PBC). In simulated tumor microenvironment, the system released anticancer drug DOX to be a DNA intercalator and topoisomerase II inhibitor to realize chemotherapy (CT) and iron ions were delivered to induce Fenton reaction, which boost the generation of •OH, resulting in the enhancement of the effect of chemodynamic therapy (CDT). Meantime, the system could consume glutathione (GSH) to reduce the expression of glutathione peroxidase 4 (GPX4); then, lipid peroxides (LPO) were accumulated to realize ferroptosis. DOX@Fe-PBC provided an effective strategy of chemotherapy, CDT, and ferroptosis to realize ideal cancer treatment.
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iScience
·
2025
·
IF 4.1
Kuan Yoow Chan,Yini Yu,Yidi Kong,Ling Cheng,Renzhi Yao,Phoebe Sha Yin Chair,Ping Wang,Rong Wang,Wan-Yang Sun,Rong-Rong He,Junxia Min,Fudi Wang,Mikael Björklund
Despite wide variation, each cell type has an optimal size. Maintaining optimal size is essential for cellular fitness and function but the biological basis for this remains elusive. Here, we performed fitness analysis involving genome-wide CRISPR/Cas9 knockout data from tens of human cell lines and identified that cell size influences the essentiality of genes related to mitochondria and membrane repair. These genes also included glutathione peroxidase 4 (GPX4), which safeguards membranes from oxidative damage and prevents ferroptosis — iron-dependent death. Growth beyond normal size, with or without cell cycle arrest, increased lipid peroxidation resulting in a ferroptosis-sensitive state. Proteomic analysis revealed cell cycle -independent superscaling of endoplasmic reticulum, accumulation of iron and lipidome remodeling. Even slight increases from normal cell size sensitized proliferating cells to ferroptosis as evidenced by deep-learning-based single-cell analysis. Thus, lipid peroxidation may be a fitness trade-off which constrains cell enlargement and contributes to the establishment of an optimal cell size.
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ACS Biomaterials Science & Engineering
·
2025
·
IF 5.5
Jingchao Li,Yinghua Zeng,Fengjiao Liu,Xu Liao,Chongbin Zhong,Shujuan Dong,Yanbin Cai,Pingzhen Yang
Doxorubicin (DOX) chemotherapy is a cornerstone of cancer treatment, but its clinical application and effectiveness are severely restricted due to its life-threatening cardiotoxicity. Xanthohumol (XH), a compound from traditional Chinese medicine, is noted for its antioxidant properties and the potential to mitigate DOX-induced cardiotoxicity (DIC). However, its poor water solubility results in low biocompatibility, making it susceptible to immune system clearance, which severely restricts its application in vivo. In this study, we first identified and demonstrated that XH can effectively mitigate DIC by inhibiting ferroptosis. We designed a biomimetic nanodelivery system encapsulating XH within porous poly(lactic-co-glycolic acid) (PLGA) nanoparticles, further coated with an erythrocyte membrane (XH-NPs@RBCm). This system offers several advantages, including evasion of macrophage phagocytosis and prolonged circulation time, thereby enhancing the stability and bioavailability of XH in vivo. Treatment with XH-NPs@RBCm significantly reduced reactive oxygen species-dependent ferroptosis, improving the DOX-induced myocardial atrophy and cardiac dysfunction. Our study underscores the therapeutic promise of XH-NPs@RBCm in treating DIC through ferroptosis inhibition, offering key insights into biomimetic nanodelivery system development for DIC management.
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ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Hui Xu,Na Liu,Qian Wang,Jinyang Liu,Chen Qu,Wenchao Zhang,Jing Qian
Fenton-induced ferroptosis has emerged as a promising therapeutic strategy for malignant tumors. However, the therapeutic efficacy of ferroptosis is limited by factors such as suboptimal Fenton efficiency, intracellular antioxidant systems, and insufficient drug accumulation. Here, we report a domino effect triggered by a homologous cancer cell membrane-camouflaged nanoformulation: disrupting intracellular redox homeostasis, inducing enhanced oxidative stress and leading to specific ferroptosis. This strategy involves using pure red-emission upconversion nanoparticles (NaErF4:4%Tm@NaYF4, U NPs), a ferroptosis inducer (ferrous fumarate, an iron-deficiency anemia therapeutic reagent), and glucose oxidase (GOx). The nanoformulation, U@mSiO2/ferrous fumarate/GOx@lecithin/cell membrane (USFGM), enables efficient in vivo deep tissue upconversion luminescence (UCL) imaging by pure red-emission. Lecithin-modified cancer cell membranes are characterized by homologous target “homing” and acid-responsive release. Exogenous GOx depletes intratumoral glucose and generates H+/H2O2, which disrupts the nutrient supply and promotes efficient generation of reactive oxygen species (ROS). Subsequently, Fe2+/fumaric acids (FAs) are acid-responsively released from ferrous fumarate, which synchronously triggers and exacerbates the process of ferroptosis through mechanisms such as lipid ROS generation and glutathione (GSH) depletion. Here, we report for the first time that FA depletes GSH and leads to inactivation of GSH-dependent peroxidase 4 (GPX4). This concept is also confirmed in tumor-bearing mice of salivary adenoid cystic carcinoma (SACC). In summary, this work identifies a systemic, low-toxicity, and highly efficient cancer inhibitory nanoformulation from existing clinical drugs, which provides a promising direction for exploring therapeutic strategies for human malignant tumors.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
·
IF 6.8
Yi He,Fangyang Shi,Jiajun Hu,Hongyu Li,Xun Chen,Lingyu Yuan,Yunyang Lu,Weidong Du,Runze Li,Jie Wu,Feilong Deng,Dongsheng Yu
Magnetic graphene oxide nanocomposites (MGO NPs) have been widely studied in biomedical applications. However, their cytotoxicity and underlying mechanisms remain unclear. In this study, the biosafety of MGO NPs was investigated, and the mechanism involved in ferroptosis was further explored. MGO can produce cytotoxicity in ADSCs, which is dependent on their concentration. Ferroptosis was involved in MGO NP-induced ADSC survival inhibition by increasing total ROS and lipid ROS accumulation as well as regulating the expression levels of ferroptosis-related genes and proteins. GPX4 played a critical role in the MGO NP-induced ADSC ferroptosis process, and overexpressing GPX4 suppressed ferroptosis to increase cell survival. This study provides a theoretical basis for the biosafety management of MGO NPs used in the field of biomedical treatment.
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CELLULAR SIGNALLING
·
2026
·
IF 4.7
Qiu-shuang Ma,Xiao-man Zhao,Wan-ying Zhang,Li-jun Shao,Yi-fan Liu,Li-ya Feng,Xiao-xia Yang,Xiu-li Guo
Enolase 1 (ENO1) is overexpressed in hepatocellular carcinoma (HCC) and correlates with poor patient prognosis, as evidenced by TCGA and Kaplan-Meier (KM) analysis. This study demonstrates that targeting ENO1 with its specific inhibitor, ENOblock, markedly enhances the antitumor efficacy of sorafenib in HCC cells. The combination of sorafenib and ENOblock significantly suppresses cell proliferation, migration, invasion, and angiogenesis in vitro and in vivo . Mechanistically, sorafenib and ENOblock synergistically promote ferroptosis by concurrently regulating the Keap1/Nrf2/NQO1 and TFR1/C-MYC/NCOA4/FTH1/LC3 pathways, independent of xCT/GPX4 pathway. These effects are characterized by elevated levels of reactive oxygen species (ROS), iron ions, and malondialdehyde (MDA). In vivo tumorigenic models further confirm that the enhanced therapeutic effect of sorafenib by ENOblock. Our findings not only elucidate a novel ferroptosis-based mechanism underlying sorafenib response in HCC, but also position ENOblock-sorafenib combination as a promising preclinical proof- of-concept strategy targeting ENO1 for HCC intervention.
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ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Hao Chen,Guangrong Zheng,Fang Qin,Yuanjun Yu,Haiyan Yang,Xiang Mao
Traditional chemotherapy agents often face multiple drug resistance mechanisms in breast cancer and are associated with significant side effects. Innovative phototherapy and enzyme therapy demonstrate potential in ameliorating hypoxic conditions in the tumor microenvironment while inducing oxidative stress. Here, we designed a NIR-triggered multifunctional nanoplatform for the synergistic combination of phototherapy and enzyme therapy in tumors. It encapsulates Au-Au@PEG nanocomponents and integrates gold nanoparticles (AuNPs) and gold nanoclusters (AuNCs) coated with polydopamine (PDA), followed by doxorubicin (DOX) loading. We refer to this formulation as DOX-PDA@Au-Au@PEG (DOX-PAAP). DOX-PAAP is capable of releasing drugs through degradation of the coating under low pH and high glutathione (GSH) conditions. The synergistic effect between the PDA coating and AuNPs significantly enhances the photothermal effect associated with NIR light absorption, thereby improving the therapeutic efficacy. Meanwhile, AuNCs can not only catalyze the decomposition of H2O2 to generate hydroxyl radicals in conjunction with the PDA coating but also produce singlet oxygen under NIR irradiation. This mechanism disrupts the GSH antioxidant axis, thereby promoting the accumulation of lipid peroxidation products (LPO), culminating in dual apoptosis–ferroptosis pathway activation. This study highlights the critical role of NIR phototherapy and enzyme therapy in combination therapies for ferroptosis and apoptosis therapy targeting tumors.
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Advanced Healthcare Materials
·
2021
·Vol. 11
·期 2
·2101702
·
IF 9.933
Yuchen Zhang,Liqi Li,Yanan Li,Yang Fei,Chencheng Xue,Xuemei Yao,Youbo Zhao,Xuan Wang,Menghuan Li,Zhong Luo
Ferroptosis is an emerging antitumor option and has demonstrated unique advantages against many tumor indications. However, its efficacy is potentially hindered by the endogenous lipid peroxide-scavenging mechanisms and the reliance on acidic pH. Herein, a nanointegrated strategy based on clinically-safe components to synergistically remodel glutathione and lactate metabolism in tumor cells for enhanced ferroptosis therapy is developed. First ferrocene is conjugated on PEGylated polyamidoamine dendrimers via reactive oxygen species (ROS)-cleavable thioketal linkage, which would further self-assemble with the glutathione (GSH)-depleting agent diethyl maleate (DEM) and monocarboxylate transporter 4-inhibiting siRNA (siMCT4) to afford biostable nanoassemblies (siMCT4-PAMAM-PEG-TK-Fc@DEM). The nanoassemblies can be activated by the elevated ROS levels in tumor intracellular environment and readily release the incorporated therapeutic contents, afterward DEM can directly conjugate to GSH to disrupt the glutathione peroxidase 4 (GPX4)-mediated antioxidant defense, while siMCT4 can block the MCT4-mediated efflux of lactic acid and acidify the intracellular milieu, both of which can improve the ferrocene-catalyzed lipid peroxidation and induce pronounced ferroptotic damage. The siMCT4-PAMAM-PEG-TK-Fc@DEM nanoplatform demonstrates high ferroptosis-based antitumor potency and good biocompatibility in vitro and in vivo, which may offer new avenues for the development of more advanced antitumor therapeutics with improved translatability.
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