ANTIOXIDANTS & REDOX SIGNALING
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2026
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IF 6.1
Ze Wang,Kejie Chang,Ke Zhang,Pei Wang,Guangjian Bai,Zhenhua Wang,Jian Xiao,Xin Tong,Jun Zhao
Aims:Esophageal squamous cell carcinoma (ESCC) is among the most lethal malignancies worldwide, with a five-year survival rate below 20%. Ferroptosis—a regulated form of cell death driven by iron-dependent lipid peroxidation—has emerged as a promising therapeutic strategy, yet its regulation in ESCC remains poorly understood. We investigated the role of tripartite motif-containing 31 (TRIM31), an E3 ubiquitin ligase, in ESCC progression and ferroptosis.Results:TRIM31 expression was significantly elevated in ESCC tissues compared with normal esophageal tissues (The Cancer Genome Atlas and Genotype-Tissue Expression datasets; p < 0.001) and correlated with advanced Tumor, Node, and Metastasis (TNM) stage (p = 0.004), lymph node metastasis (p = 0.024), and poor overall survival (p = 0.0027). Functional assays revealed that TRIM31 knockdown reduced ESCC cell proliferation, impaired colony formation, and suppressed migration (p < 0.01). In vivo, TRIM31 silencing decreased xenograft tumor volume by over 70% and Ki-67 expression by 73%. Mechanistically, TRIM31 directly interacted with VDAC1 via its coiled-coil domain, promoting VDAC1 ubiquitination and proteasomal degradation. This interaction inhibited ferroptosis, as evidenced by increased lipid reactive oxygen species, elevated intracellular Fe2+ levels, and mitochondrial damage upon TRIM31 knockdown. Conversely, TRIM31 overexpression attenuated ferroptosis induced by RSL3. We further identified hepatocyte nuclear factor 4 alpha as a transcriptional activator of TRIM31, binding to its promoter region. Importantly, TRIM31 knockdown synergized with the ferroptosis inducer imidazole ketone erastin, achieving a 90% reduction in tumor growth without significant toxicity.Conclusion:TRIM31 promotes ESCC progression by degrading VDAC1 and suppressing ferroptosis. Targeting TRIM31 enhances ferroptosis-based therapy and represents a novel, clinically actionable strategy for ESCC treatment. Antioxid. Redox Signal. 00, 000–000.
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ORAL DISEASES
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2024
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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.
研究领域:
牙科学
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肾病学
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细胞生物学
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分子生物学
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Cell Host & Microbe
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2026
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IF 18.7
Siyuan Fan,Xinyue Cai,Weiqi Wang,Meiling Wu,Xiaoyao Huang,Feng Ding,Hao Guo,Geng Dou,Haotian Luo,Shuai Shao,Jing Guo,Zhenlai Zhu,Peisheng Liu,Linfeng Cheng,Siying Liu,Zihan Li,Kun Xuan,Shiyu Liu
Ultraviolet irradiation, particularly ultraviolet B (UVB), damages keratinocytes, potentially causing actinic cheilitis. Commensal bacteria help maintain barrier function and protect the host. However, it is unclear if commensal bacteria can protect the host from UVB irradiation. Here, we demonstrate that Rothia mucilaginosa ( R. mucilaginosa )-derived membrane vesicles (RMVs) contain ferrochelatase, which stabilizes labile iron in host cells to alleviate UVB-induced ferroptosis. We demonstrate that R. mucilaginosa abundance on lip vermilion inversely correlates with actinic cheilitis severity in patients. Mechanistically, we find that UVB induces R. mucilaginosa to release RMVs, which are internalized by host cell lysosomes. The ferrochelatase contained within these RMVs catalyzes conversion of Fe 2+ and porphyrin into heme, thereby alleviating UVB-induced iron overload and ferroptosis. Topical application of RMVs relieves actinic cheilitis in patients (ChiCTR, no. ChiCTR2500100015). Collectively, we reveal an iron stabilization mechanism through which commensal bacteria protect the host against UVB and expand our understanding of the relationship between commensal bacteria and hosts.
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CELL DEATH AND DIFFERENTIATION
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2026
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IF 13.6
Luan Jing,He Jiyuan,Wu Dantong,Duan Yaning,Hou Guoyuan,Ma Shuang,Qin Jianhua,Sun Na,He Yuanzheng,Zhang Wei,Gao Minghui
Ferroptosis is a type of regulated necrosis driven by iron-dependent lethal accumulation of lipid peroxides. Selenoprotein thioredoxin reductase (TrxR) plays crucial roles in cellular redox homeostasis. However, its role in ferroptosis remains unclear. Here, we report TrxR1 positively regulates ferroptosis. The selenocysteine of TrxR1 is required for its regulation of ferroptosis. Mechanistically, the CRL4A CRBN E3 complex ubiquitinates KEAP1 at K84 and K312, driving KEAP1 degradation. Overexpression of TrxR1 increases KEAP1 stability by suppressing CRL4A CRBN E3 complex mediated KEAP1 ubiquitination and degradation, enhances the interaction between NRF2 and KEAP1, promotes NRF2 ubiquitination and drives NRF2 degradation, which results in downregulation of GPX4 expression, thereby sensitizing cells to ferroptosis. Furthermore, high level of TrxR1 sensitizes cancer cells to ferroptosis in vivo. CRBN inhibitor thalidomide and IKE combination treatment results in markedly retarded tumor progression. Our study reveals a crucial pro-ferroptotic role for TrxR1 and nominates it as a potential biomarker for guiding future ferroptosis-inducing therapies in select cancers.
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Advanced Healthcare Materials
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2026
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IF 11
Jiarong Liang,Si Wang,Zhonghui Ma,Fei Kuang,Xiangkun Li,Zhilong Gong,Jinzhu Su,Zhiyi Wang
Combining efficient photocatalytic activity with precise targeting is crucial for covalent organic framework (COF)-based nanomedicines to remodel the immunosuppressive microenvironment and sensitize “cold” tumors to immunotherapy. Herein, we constructed two isomorphic frameworks featuring distinct electronic topologies: a zwitterionic squaric acid (SA) COF with inherent electrostatic asymmetry, and a charge-neutral terephthaldehyde (TA) COF. The spatial divergence of ion centers in SA COF triggers intense molecular-level ionic displacement polarization, creating a robust internal electric field. Such unique field-effect regulation accelerates photogenerated charge separation for efficient superoxide anion production, enhances intersystem crossing for singlet oxygen generation, and promotes nonradiative energy relaxation for high-performance photothermal conversion under dual-wavelength irradiation. After PEGylation and iRGD modification, the formulated SA@PEG-iRGD exhibits excellent physiological stability and active deep tumor penetration. With near-infrared absorption, it enables high-contrast photoacoustic imaging for guided dual-wavelength (660/808 nm) phototherapy. This spatiotemporally controlled therapeutic cascade triggers lethal ferroptosis and precise photothermal ablation, potently activating immunogenic cell death. Combined with aPD-L1 therapy, it eliminates primary tumors, produces abscopal effects, and establishes immune memory against recurrence and metastasis. This study highlights the value of electronic structure engineering in COF-based precision nanomedicine.
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ACS Applied Materials & Interfaces
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2026
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IF 7.8
Hang Wang,Yuli Kang,Qiqiang Zhang,Xuelian Wang,Yongqiang Li,Liangfeng Chen,Siwei Yang,Jia Qi,Hui Dong,Guqiao Ding
Biomedical strategies based on the cellular microenvironment often lead to significant improvements in diagnosis and therapy. In this study, based on the elevated reactive oxygen species (ROS) microenvironment of senescent cells, we designed Fe3+ coordinated nitrogen doped graphene quantum dots (Fe@N-GQDs) with both photodynamic and ferroptotic activity. The results demonstrated that Fe3+ modulated the electronic structure of nitrogen doped graphene quantum dots (N-GQDs) and enhanced their photodynamic activity. Meanwhile, the high ROS levels in endoplasmic reticulum and mitochondria enabled accumulated Fe@N-GQDs to synergistically amplify oxidative stress through the Fe3+/Fe2+ redox cycle and activate the ferroptosis related process. Under the synergistic photodynamic and ferroptosis effects, the clearance efficiency of senescent cells reached 98%. More importantly, leveraging the senescent cell microenvironment, Fe@N-GQDs showed minimal impact on healthy cells without targeting modifications, significantly improving therapeutic safety.
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Cancer Nanotechnology
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2026
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IF 5.8
Ren Jinxiao,Li Shiping,Shen Juping
Ferroptosis is an iron-dependent form of regulated cell death driven by excessive lipid peroxidation and reactive oxygen species (ROS) accumulation. Herein, we report a novel metal-coordinated nanoparticle system (OFe-NPs) fabricated via a one-pot self-assembly between orlistat and FeCl 3 ·6 H₂O for ferroptosis-based tumor therapy. The optimized OFe-NPs exhibited uniform nanoscale size and good colloidal stability under physiological conditions. In MCF-7 breast cancer cells, OFe-NPs showed significantly enhanced cytotoxicity compared with free orlistat, which was attributed to glutathione (GSH)-responsive disassembly and intracellular release of Fe ions and orlistat. Mechanistic investigations revealed that OFe-NPs effectively induced ferroptosis, as evidenced by increased lipid peroxidation, intracellular Fe 2+ accumulation, glutathione depletion, malondialdehyde elevation, and marked downregulation of GPX4. In an MCF-7 xenograft mouse model, OFe-NPs treatment significantly suppressed tumor growth, achieving a tumor inhibition rate of 76.76% with no evident systemic toxicity. These findings demonstrate that metal-coordinated orlistat–Fe(III) nanoparticles synergistically amplify ferroptosis via simultaneous iron-mediated oxidative stress and GPX4 suppression, offering a promising strategy for cancer therapy.
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EXPERIMENTAL ANIMALS
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2026
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IF 2
Cong SHI,Jianhua SUN,Jumin NIU
Intrauterine adhesion (IUA) is a significant contributor to uterine infertility, primarily characterized by endometrial fibrosis. Although diacerein exhibits anti-inflammatory and anti-fibrotic properties, its therapeutic potential in IUA remains unclear. This study investigated the protective effects of diacerein in an IUA rat model induced by mechanical injury. Histological analysis revealed that diacerein treatment alleviated endometrial damage, and immunohistochemical staining confirmed the restoration of CK19 and CK18 expression, indicating improved epithelial integrity and regeneration. Diacerein mitigated endometrial fibrosis by inhibiting epithelial-mesenchymal transition (EMT), as evidenced by increased E-cadherin and decreased N-cadherin expression, likely via suppression of TGFβ/SMAD2 signaling. Diacerein exerted anti-inflammatory effects in IUA rats. Notably, diacerein inhibited ferroptosis by reducing lipid peroxidation, limiting Fe²⁺ accumulation, and modulating ferroptosis-related proteins, including ACSL4, SLC7A11, GPX4, and FTH1. The protective effects of diacerein were mirrored by ferroptosis inhibitor Ferrostatin-1 treatment but reversed by ferroptosis inducer Erastin, confirming that diacerein alleviates endometrial fibrosis in IUA rats through ferroptosis suppression. Mechanistically, diacerein modulated the NRF2/HMGB1 signaling pathway, restoring NRF2 and HO1 levels while downregulating HMGB1 expression. Collectively, these findings suggest that diacerein effectively attenuates ferroptosis-mediated fibrosis in IUA, highlighting ferroptosis inhibition as a promising therapeutic strategy for IUA management.
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Scientific Reports
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2026
·Vol. 16
·期 1
·16800
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IF 4.9
Rong Wenqing,Zhang Minquan,Yang Siqi,Wang Kaiwen,Yang Xiaoping,Zhang Guolei,Li Zhe,Ding Yue,Zhang Tong,Gai Yun,Lan Jinshuai
Breast cancer (BC), the most common cancer in women, is closely related to ferroptosis, which is an iron-dependent form of cell death. Gambogic acid (GA), the main active ingredient extracted from the dry resin secreted by Garcinia cambogia, can effectively induce ferroptosis in tumor cells. However, its application is limited by poor water solubility, short half-life, and vascular irritation. Moreover, the sensitivity of cells to ferroptosis is positively correlated with the concentration of intracellular iron ions, which based on transferrin (Tf)-Tf receptor (TfR) pathway. Increasing intracellular iron ions within tumor cells may enhance GA-induced ferroptosis. Based on the high expression of TfR in tumor cells, Tf can be both a tumor-target modification and an Fe 3+ carrier. Therefore, GA-loaded Tf-modified liposomes (GA@Tf-Lip) with pH-responsive properties were developed. GA@Tf-Lip increased the intracellular iron ion content of MCF-7 cells, promoted the Fenton reaction to increase the level of ROS, downregulated the GSH content, and accelerated lipid peroxide accumulation. The distribution of the formulation by in vivo imaging experiments showed that the prepared GA@Tf-Lip had a higher drug accumulation at tumor sites and exhibited a good antitumor effect by promoting ferroptosis. Overall, GA@Tf-Lip exerted a good anti-BC effect, which is expected to provide a new strategy for the treatment of BC and the clinical transformation of GA.
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MICROCHIMICA ACTA
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2026
·Vol. 193
·期 8
·586
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IF 5.4
Geng Yan,Du Pengye,Aishajiang Reyida,Jiang Min,Liu Yu,Hao Linlin,Lei Pengpeng,Zhang Hongjie,Guo Jie
Triple-negative breast cancer (TNBC) displays pronounced molecular heterogeneity and metastatic propensity, which correlates with its poor clinical prognosis. Crucially, radiotherapy (RT) resistance serves as a pivotal contributor to treatment failure and disease advancement in TNBC. To address this challenge, we developed BWFP, which is achieved by loading WZB117 and FIN56 onto bismuth-based metal organic framework with radiosensitization effect and surface modifying pH-responsive DSPE-PEOz. Under the acidic tumor microenvironment, BWFP controllably releases its payload: WZB117 suppresses glucose uptake through GLUT1 downregulation, thereby limiting NADPH production and inducing cystine accumulation alongside cysteine depletion, which concurrently triggers disulfidptosis and relieves ferroptosis resistance. Meanwhile, the released ferroptosis inducer FIN56 further amplifies ferroptosis by degrading GPX4. In addition to this, BWFP enhances RT efficacy through radiosensitization effects, consequently intensifying DNA damage. In a word, BWFP demonstrates robust anti-tumor activity in TNBC models by concomitantly inducing disulfidptosis and ferroptosis with synergized radiosensitization. Graphical abstract
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Frontiers in Oncology
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2026
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IF 3.4
Bixia Chi,Zhi Cui,Xinyue Hou,Hongfang Ding,Linjun Li,Rui Ai,Yizhuang Yang,Yue Zhao,Liyan Wang,Juan Wang
Acidic leucine-rich nuclear phosphoprotein 32A(ANP32A) is known to possess multi-functions and has been observed to exhibit different roles across various malignancies. Although the expression of ANP32A has been shown to correlate with metastatic spread and reduced survival in Hepatocellular carcinoma(HCC), the underlying mechanisms have not been fully elucidated. This study utilized univariate Cox regression, differential gene analysis, and WGCNA to identify ANP32A as closely associated with poor HCC prognosis. Our Co-IP results confirmed the interaction between ANP32A and LDHA. Additionally, silencing ANP32A inhibited HCC cell proliferation in vitro as well as in vivo, and altered glycolytic and ferroptotic pathways, with increased LDHA ubiquitination detected. These data suggested that ANP32A may play a role in HCC progression, positioning it as a highly attractive therapeutic target for advanced HCC. Silencing ANP32A augmented the susceptibility of HCC cells to ferroptosis and inhibited aerobic glycolysis, which may provide new avenues for combination therapies, offering potential for improved patient outcomes.
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ENVIRONMENT INTERNATIONAL
·
2026
·
IF 10.2
Pengyu Wang,Xia Zhang,Ning Ding,Aimei Liu,Shuo Zhang,Yan Song,Leiming Yang,Huiting He,Mi Chen,Xiying Guo,Youzhi Zhang
Trimethyltin chloride (TMT), a poison from water and soil, has been linked to bradycardia. Ferroptosis, an iron-driven type of regulated cell death, is critically involved in cardiovascular diseases. However, the mechanism of TMT-induced myocardial injury remains unclear. This study aims to investigate the toxicological mechanism of TMT-induced myocardial injury and evaluate the protective effect of Lut. In this study , RNA sequencing identified Gpx4 as the key ferroptosis-related gene of TMT-induced cardiomyopathy. In vitro , TMT induced ferroptosis, which was reversed by Ferrostatin-1. Notably, TMT also suppressed mitophagy, co-treatment with chloroquine (CQ) aggravated TMT-induced ferroptosis, whereas Urothione A reversed this effect. In vivo and in vitro , TMT caused bradycardia and myocardial ferroptosis, while Luteolin (Lut) exerted anti-ferroptosis effects. Furthermore, TMT increased DRP1 phosphorylation and reduced the expression of mitochondrial fusion and mitophagy proteins, which were restored by Lut. And the anti-ferroptosis effect of Luteolin was abolished by CQ. Collectively, it revealed that TMT induced ferroptosis in vitro and vivo, while Lut alleviated TMT-induced myocardial injury by activating mitophagy, inhibiting ferroptosis, then restoring mitochondrial function.
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