ACS Applied Materials & Interfaces
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2025
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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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CELLULAR SIGNALLING
·
2026
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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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Advanced Healthcare Materials
·
2021
·Vol. 11
·期 2
·2101702
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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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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
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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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ORAL DISEASES
·
2024
·
IF 2.9
Huiwen Chen,Yining Zhou,Yingli Liu,Wei Zhou,Lina Xu,Dihua Shang,Jing Ni,Zhongchen Song
Objectives The purpose of this study was to determine whether indoxyl sulfate (IS) is involved in alveolar bone deterioration and to elucidate the mechanism underlying alveolar bone loss in chronic kidney disease (CKD) patients. Materials and Methods Mice were divided into the control group, CP group (ligature-induced periodontitis), CKD group (5/6 nephrectomy), and CKD + CP group. The concentration of IS in the gingival crevicular fluid (GCF) was determined by HPLC. The bone microarchitecture was evaluated by micro-CT. MC3T3-E1 cells were stimulated with IS, and changes in mitochondrial morphology and ferroptosis-related factors were detected. RT-PCR, western blotting, alkaline phosphatase activity assays, and alizarin red S staining were utilized to assess how IS affects osteogenic differentiation. Results Compared with that in the other groups, alveolar bone destruction in the CKD + CP group was more severe. IS accumulated in the GCF of mice with CKD. IS activated the aryl hydrocarbon receptor (AhR) in vitro, inhibited MC3T3-E1 cell osteogenic differentiation, caused changes in mitochondrial morphology, and activated the SLC7A11/GPX4 signaling pathway. An AhR inhibitor attenuated the aforementioned changes induced by IS. Conclusions IS activated the AhR/SLC7A11/GPX4 signaling pathway, inhibited osteogenesis in MC3T3-E1 cells, and participated in alveolar bone resorption in CKD model mice through ferroptosis.
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BIOCHEMICAL PHARMACOLOGY
·
2025
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IF 5.6
Haoyu Yang,Xin Chen,Siqi Huang,Hongfang Dai,Zuowei Xiao,Jialong Fan,Honggang Zhang,Ke Du,Yan Qin
Ferroptosis and cuproptosis are two important new forms of ion-dependent cell death, whose processes can be inhibited by high levels of glutathione (GSH) within cells. Therefore, reducing GSH levels is a key strategy for inducing ferroptosis and cuproptosis. Herein, we successfully developed a curcumin (Cur) derivative, bisdemethylcurcumin (bm-Cur), as a novel GSH depletor that simultaneously induces ferroptosis and cuproptosis in hepatocellular carcinoma (HCC). The unique polyphenolic hydroxy structure and double α, β-unsaturated ketone structure of bm-Cur confers its potent GSH scavenging ability, which can effectively deplete GSH by simultaneously inhibiting GSH synthesis and directly consuming GSH levels, ultimately inducing ferroptosis and cuproptosis. Notably, bm-Cur can target mitochondria, induce mitochondrial lipid peroxidation and mitochondrial damage, thereby promoting ferroptosis and cuproptosis-mediated cell death, which demonstrates potential for anti-HCC activity in vitro and in vivo . Moreover, bm-Cur exhibited very low cytotoxicity, excellent biosafety and biocompatibility. In conclusion, this study suggests that bm-Cur may be a novel ferroptosis and cuproptosis activator with significant development potential for further application.
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FISH & SHELLFISH IMMUNOLOGY
·
2025
·
IF 3.9
Yang Feng,Senyue Liu,Xiaoli Huang,Yi Geng,Chengyan Mou,Han Zhao,Jian Zhou,Qiang Li,Yongqiang Deng
Overwintering syndrome (OWS) causes massive mortality in grass carp ( Ctenopharyngodon idella ) during early spring, yet its pathogenesis beyond the "low-temperature–pathogen" paradigm remains unclear. This study investigates the cascade mechanism through integrated multi-omics analyses on gill tissues of healthy and OWS-affected grass carp. Gill histopathology revealed progressive necrotizing inflammation in OWS-affected grass carp. Transcriptomics identified 962 differentially expressed genes, highlighting upregulation of cytokine signaling, porphyrin metabolism, and ferroptosis alongside downregulation of adrenergic pathways. Ferroptosis was confirmed through the suppression of glutathione peroxidase 4 (GPX4) and the accumulation of iron in necrotic lamellae. Mucous cell depletion and eosinophil disintegration compromised the mucosal barriers of the gills. Metagenomic analysis first revealed a state of microbial dysbiosis, marked by bacterial dominance comprising 92.21% of the community, along with an enrichment of biofilm and exotoxin genes and a reduction in immune modulation, all exacerbating barrier dysfunction. Subsequent integrated correlation analysis linked the specifically enriched bacteria taxa, including Caldilinea sp. CFX5 and Ilumatobacter sp., to the upregulation of metabolic and virulence pathways, while also revealing significant microbiota–gene interactions that modulate gill immune and metabolic functions. Although previously reported pathogens like Flavobacterium and Aeromonas showed increased abundance in OWS-affected fish, their overall abundance remained low. Based on these findings, we propose a "Dysbiosis–Ferroptosis–Collapse" axis, in which microbiota-driven barrier disruption promotes iron overload and the suppression of GPX4, triggering non-resolving inflammation and ion dyshomeostasis. Targeting this cascade provides a novel theoretical framework for intervening in and developing new treatments for OWS.
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Acta Pharmaceutica Sinica B
·
2026
·
IF 14.6
Ruizhe Xu,Xuejing Li,Xiaomin Su,Xifeng Qin,Ying He,Siyu Wang,Yue Liu,Jiayi Wu,Ting Wang,Mingyang Liu,Boshu Ouyang,Jia Li,Wuli Yang,Bo Zhang,Zhiqing Pang
The efficient targeted delivery and on-demand release of nanomedicines still present significant challenges in tumor therapy. In the present study, we developed a novel strategy of tumor ferroptosis therapy through the synergistic effect of nanomedicines (biomimetic liposomes) and a medical device (high-intensity focused ultrasound, HIFU). It was found that HIFU irradiation induced heightened expressions of CD44 and reactive oxygen species (ROS) in tumor cells by 1.43-fold and 2.64-fold, respectively. This allowed the gambogic acid-loaded, platelet-mimicking liposomes (PLip) to more precisely target the tumor cells through the interaction of CD44 and P-selectin on the PLip and subsequently ROS-responsively release the drug from PLip, thus effectively killing tumor cells. Crucially, gambogic acid also significantly enhanced ROS production, leading to lipid peroxidation and augmented ferroptosis induced by HIFU. In summary, HIFU demonstrates immense potential in synergizing with nanomedicines to combat tumors.
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Bioactive Materials
·
2026
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IF 20.3
Weiwei Yu,Xiang Li,Xufang Liu,Xinyi Hao,Wen Qin,Guoqing Qi,Gaopeng Dang,Ziyuan Tian,Shiyin Jin,Conrado Aparicio,Kaiyan Wang,Wen Niu,Lina Niu
Oral ulceration is a prevalent mucosal disorder, and its healing process is frequently hampered by poor local drug retention and inadequate mucosal adhesion. However, the underlying pathological mechanisms remain incompletely elucidated. In this study, transcriptomic sequencing revealed that ferroptosis serves as a key driver of oral ulcer progression. To address the limitations of conventional formulations in the wet and dynamic oral environment, we constructed an asymmetrically adhesive, ferroptosis-targeting, spermidine (SPD)-functionalized Janus hydrogel microneedle system (MN-HTSO-C). This system was fabricated via chemical grafting and dynamic Schiff base crosslinking, enabling targeted drug delivery into mucosal tissues. By specifically delivering SPD, this system effectively inhibited ferroptosis, reduced reactive oxygen species (ROS) accumulation, reprogrammed the local immune microenvironment, and thereby promoted angiogenesis and epithelial regeneration. Our work not only identifies a novel pathological mechanism but also proposes an integrated therapeutic strategy that combines targeted delivery, immunomodulation, and ferroptosis inhibition, providing a new direction for the treatment of oral ulcers and other ferroptosis-related mucosal diseases.
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EXPERIMENTAL CELL RESEARCH
·
2026
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IF 3.5
Fang Tong,Xue Gao,Yuhong Shang
Endometrial cancer (EC) represents one of the most prevalent malignancies of the female reproductive system. Ferroptosis, a recently identified form of programmed cell death, has garnered increasing attention in cancer research. Ubiquitin-specific peptidase 18 (USP18), a member of the deubiquitinating enzyme family, has been recognized as an oncoprotein in various cancers; however, its functional role and underlying mechanisms in EC remain largely unexplored. In this study, we found that USP18 was markedly upregulated in EC patients (n=15, stage I; n=4, stage II and n=1, stage III), and elevated USP18 expression correlated with unfavorable prognosis. Functional assays demonstrated that knockdown of USP18 significantly inhibited EC cell proliferation. Moreover, USP18 silencing promoted the accumulation of lipid reactive oxygen species (ROS), malondialdehyde (MDA), and Fe 2+ , thereby enhancing erastin-induced ferroptosis. In contrast, USP18 overexpression produced opposing effects. These in vitro findings were further validated in vivo, where USP18 knockdown suppressed tumor growth and promoted ferroptosis. Mechanistic investigations revealed that USP18 interacted with and deubiquitinated histone deacetylase 3 (HDAC3), thus leading to its stabilization. Subsequent rescue experiments confirmed that the tumor-promoting effects of USP18 were abrogated upon HDAC3 knockdown. Taken together, our results identify the USP18/HDAC3 axis as a key regulator of EC cell proliferation and ferroptosis suppression, underscoring the potential of USP18 as a therapeutic target in EC.
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Scientific Reports
·
2026
·
IF 4.9
Qin Yong,Xu Shengqian,Ye Hailin,Wang Chaojun,Pan Wenjuan
Hepatocellular carcinoma remains a leading cause of cancer-related mortality worldwide. Although lenvatinib is widely deployed as a frontline systemic therapy for advanced disease, its clinical utility is frequently subverted by primary or adaptive non-responsiveness. Evasion of ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key survival mechanism for tumor cells under therapeutic stress. While the RNA-binding protein RBMS1 is known to participate in oncogenic progression and ferroptotic regulation across several malignancies, whether it modulates lenvatinib sensitivity in hepatocellular carcinoma by intersecting with the SLC7A11-dependent antioxidant pathway has not been established. Expression profiles of RBMS1 and SLC7A11 were interrogated in paired clinical tissue samples and public transcriptomic datasets. Stable lentiviral overexpression or short hairpin RNA-mediated knockdown was executed in HepG2 and Huh7 cells to modulate candidate gene abundance. Cellular phenotypes, comprising viability, clonogenicity, migration, invasion, and drug sensitivity, were mapped via cell counting kit-eight, colony formation, wound healing, and transwell migration assays. Ferroptotic kinetics and oxidative shifts were tracked by measuring intracellular reactive oxygen species and lipid peroxidation using fluorescent probes. Finally, a subcutaneous xenograft model was established to validate the synergistic potential of RBMS1 depletion with lenvatinib therapy in vivo. In clinical specimens, SLC7A11 was markedly upregulated and tied to shortened overall survival, while RBMS1 expression exhibited a strong upward trend that correlated robustly with SLC7A11 abundance in broader transcriptomic cohorts. Functionally, overexpressing RBMS1 accelerated malignant behaviors, expanded SLC7A11 protein levels, neutralized reactive oxygen species, and shielded cells from lipid peroxidation, ultimately lowering lenvatinib sensitivity. Conversely, silencing RBMS1 yielded opposite phenotypes, aggravating ferroptotic oxidative damage and amplifying lenvatinib responsiveness. Epistatic rescue experiments demonstrated that SLC7A11 knockdown completely abrogated the anti-ferroptotic defense and drug tolerance conferred by RBMS1 hyperactivation. In vivo animal models corroborated these dynamics, showing that RBMS1 knockdown significantly potentiated the antitumor efficacy of lenvatinib. These findings position RBMS1 as a novel upstream post-transcriptional regulator of SLC7A11-dependent ferroptosis susceptibility and lenvatinib responsiveness in hepatocellular carcinoma. By reinforcing the SLC7A11 antioxidant network, RBMS1 shields malignant cells from drug-induced oxidative catastrophe. Targeting this newly uncovered post-transcriptional axis represents a viable therapeutic strategy to overcome lenvatinib tolerance in advanced disease.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Ke-xin Cao,Zhi-yuan Xia,Yuan-zhi Cheng,Yan-ping Feng,Meng Liu,Jia-cheng Yang,Yu-xuan Huang,Zhang-chao Deng,Gang Zuo,Xin Gen Lei,Lv-hui Sun
The present study investigated the protective effects and molecular mechanisms of nanoselenium (Nano-Se) against heat stress-induced reproductive damage in Hainan Wenchang roosters. Compared with sodium selenite, Nano-Se more effectively improved sperm quality, enhanced activities of testicular antioxidant enzymes (glutathione peroxidase and thioredoxin reductase), and attenuated lipid peroxidation, as indicated by decreased malondialdehyde and protein carbonyl levels under heat stress conditions. Nano-Se also inhibited testicular cell apoptosis and preserved blood-testis barrier integrity. Notably, Nano-Se reduced testicular iron accumulation and suppressed ferroptosis, as evidenced by increased expression of SLC7A11, GPX4, and NQO1 and decreased expression of DMT1 and ACSL4. Consistently, in heat-stressed GC-2 spd(ts) cells, Nano-Se attenuated ferroptosis by reducing iron accumulation, lipid peroxidation, and mitochondrial damage. Mechanistically, the protective effects of Nano-Se were associated with modulation of the SLC7A11/GSH/GPX4 axis and enhanced GPX4 expression. These findings indicate that Nano-Se is an effective antiferroptotic selenium source for mitigating heat stress-induced male reproductive damage.
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