ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Xiaoxiao Chen,Feng Zhang,Chenying Lu,Ronghua Wu,Baozhu Yang,Tingting Liao,Baojie Du,Fazong Wu,Jiayi Ding,Shiji Fang,Zhongwei Zhao,Minjiang Chen,Gaofeng Shu,Weiqian Chen,Jiansong Ji
Treatment for hepatocellular carcinoma (HCC) may be improved with ferroptosis, a regulated form of cell death. However, the sensitivity of HCC to ferroptosis was strongly limited by lactic acid. In this study, a platelet membrane (PM)-engineered nanoparticle loaded with erastin, superparamagnetic iron oxide nanoparticles (SPIO) and lactate oxidase (LOX) (termed PM@ESL NPs) was designed for magnetic resonance imaging (MRI)-guided enhanced ferroptosis-immunotherapy of HCC. It was found that PM@ESL NPs could actively accumulate into the tumor due to the tumor-homing ability of PM. Subsequently, PM@ESL NPs could effectively enhance the sensitivity of HCC to ferroptosis by removing the lactic acid in the tumor. The removal of lactic acid also produces hydrogen peroxide (H2O2), which therefore converted into the cytotoxic hydroxyl radicals by the reaction of H2O2 with Fe2+/Fe3+ released from SPIO. Due to the combined ferroptosis and chemodynamic therapy (CDT), PM@ESL NPS showed a strong ability to induce immunogenic cell death (ICD), which could effectively suppress the growth and metastasis of HCC when combined with αPD-L1 immunotherapy. Furthermore, the incorporation of SPIO endows PM@ESL NPs with an outstanding MRI-T2 monitoring capability for HCC treatment. In conclusion, this study introduces a pioneering MRI-guided approach that enhances ferroptosis in tumors and synergistically improves immunotherapy.
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Advanced Healthcare Materials
·
2026
·
IF 11
Shuang Liu,Hewen Li,Yuhang Ding,Dengyi Duan,Lin Cao,Kangkang Liu,Wenyi Zhang,Shifeng Cheng,Yiming Li,Yunfei Guo,Xiang Qi,Jianmin Li,Xuening Zhang,Jing Peng,Gang Han,Yang Zhao
Ferroptosis is triggered by iron-dependent lipid peroxidation, which shows great potential in tumor therapy. However, its biomedical applications are constrained by suboptimal therapeutic efficacy, leakage of metal ions from inducing agents, and the absence of noninvasive evaluation methods. In this study, we aimed to develop a self-reducing nano-theranostic agent (Fe@AP-SAS/RGD, FASR) for tumor-targeted ferroptosis therapy and conducted real-time magnetic resonance imaging(MRI) to monitor ferroptosis by encapsulating iron oxide particles in natural apple pectin (AP). In a weakly acidic tumor microenvironment, the strong reducing ability of AP accelerated the transformation of Fe 3+ within FASR into highly active Fe 2+ . Subsequently, the concentration of Fe 2+ increased and boosted the antitumor effect of ferroptosis. Notably, MRI of prostate cancer mouse models after intravenous injection of FASR NPs at varying doses revealed that the T 2 value decreased at the tumor sites and exhibited a linear correlation with the changes in ferroptosis hallmark markers, tumor weight, and volume after treatment. These findings demonstrate the capacity of T 2 mapping to quantitatively evaluate ferroptosis efficacy. This study not only introduced a tumor-targeted and self-reducing strategy to amplify ferroptosis but also pioneered a novel pathway for noninvasive imaging and monitoring of ferroptosis treatment processes within live tumors.
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CHEMISTRY & BIODIVERSITY
·
2026
·Vol. 23
·期 5
·e71299
·
IF 2.9
A-Long Zhang,Zheng-Biao Zou,Yan-Qing Guo,Wen-Si Su,Chun-Lan Xie,Li-Sheng Li,Cheng-Hai Gao,Xian-Wen Yang
Two new polyketides ( 1–2 ) were isolated from the deep-sea-derived fungus Penicillium citrinum W17, along with 39 known compounds ( 3 - 41 ). The structures were established by 1D and 2D NMR, HRESIMS data analysis. Compounds 10 , 35 , and 36 displayed potent inhibitory effects against RSL3-induced ferroptosis with EC 50 values of 2.7 µM, 4.9 µM, and 5.4 µM, respectively. Graphical From the deep-sea-derived fungus Penicillium citrinum W17, two new polyketides and 39 known compounds were isolated. Three compounds of 2,3,4-trimethyl-5,7-dihydroxy-2,3-dihydrobenzofuran ( 10 ), penicitrinone A ( 35 ), and penicitrinol B ( 36 ) significantly inhibit RSL3-induced ferroptosis with EC 50 values of 2.7 µM, 4.9 µM, and 5.4 µM, highlighting deep-sea fungi as promising sources of anti-ferroptosis agents.
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JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2026
·Vol. 45
·期 1
·153
·
IF 14.3
Wang Lifen,Xu Hongxia,Liu Tianyu,Zhu Dongliang,Chen Liping,Liu Tzu-ming,Lin Shuhai,Liu Xueyi,Feng Hao,Wang Li,Di Li-jun
Background Triple-negative breast cancer (TNBC) is characterized by aggressive clinical behaviour and frequent resistance to chemotherapy. While ferroptosis—an iron-dependent form of cell death driven by lipid peroxidation—holds promise as a therapeutic strategy, its efficacy is often limited by adaptive resistance mechanisms that remain incompletely understood. C-terminal binding protein (CtBP) is an oncogene associated with poor prognosis in TNBC; however, whether CtBP confers resistance to oxidative stress and ferroptosis, thereby contributing to its oncogenic function, remains unknown. Methods We utilized both in vitro cell lines and in vivo mouse models to investigate the role of CtBP in regulating oxidative stress and ferroptosis sensitivity. Integrative analyses, including transcriptomics, metabolomics, and clinical data interrogation, were employed to elucidate the mechanisms underlying CtBP-mediated resistance. Key mechanistic findings were further validated in clinical TNBC specimens using protein correlation analysis. Results We identified CtBP as a stress-inducible gene that is essential for ferroptosis resistance in TNBC. Mechanistically, CtBP promotes resistance by transcriptionally upregulating Prolyl 4-Hydroxylase Subunit Beta (P4HB). P4HB, localized to the endoplasmic reticulum (ER), functions as a chaperone to facilitate the correct folding and membrane maturation of SLC7A11, the catalytic subunit of the system xc - cystine/glutamate antiporter pivotal for glutathione (GSH) biosynthesis. We demonstrated that P4HB-mediated SLC7A11 maturation relies on its disulfide isomerase activity and ER retention signal (KDEL). Depletion of either CtBP or P4HB impaired SLC7A11 membrane trafficking, lead to accumulation of lipid peroxides and sensitization to ferroptosis. Conversely, P4HB overexpression restored SLC7A11 function and ferroptosis resistance in CtBP-deficient cells. Furthermore, significant positive correlations among CtBP, P4HB, and SLC7A11 expressions in clinical samples underscore the critical role of CtBP/P4HB/SLC7A11 axis in driving cancer aggressiveness. In vivo, targeting the CtBP/P4HB/SLC7A11 axis sensitized TNBC xenografts to the ferroptosis inducer RSL3, significantly suppressing tumor growth and lung metastasis. Conclusions This study identifies the CtBP/P4HB/SLC7A11 axis as a critical mediator of ferroptosis resistance in TNBC. These findings highlight this pathway as a potent therapeutic target to overcome resistance and enhance the efficacy of ferroptosis-inducing regimens in TNBC treatment.
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Advanced Healthcare Materials
·
2026
·
IF 11
Haobin Cai,Jing Yang,Zehui Wang,Xinyu Chen,Qingdeng Fan,Lin Huang,Fanchao Que,Haolong Ma,Tianshui Bai,Bin Ren,Xueyan Yun,Yan Li,Shipeng Ning,Zheyu Shen
Zn 2+ offers significant advantages for cancer therapy via mitochondrial disruption, immune activation, and metal homeostasis perturbation, but faces challenges of rapid clearance and systemic toxicity. Existing zinc‑based (e.g., zinc oxide (ZnO), and zinc peroxide) nanoparticles often lack internal voids and sufficient surface area, restricting drug loading and functionalization. In this study, we developed a crystallinity‑gradient selective etching method to tailor biodegradable hollow mesoporous zinc nanoparticle (HMZN). Typically, zinc peroxide nanoparticles with low‑crystallinity core and high‑crystallinity shell were synthesized, and ammonia water was used to selectively etch the inner low‑crystallinity core, producing HMZN. Hemin (HEM) and Gd‑poly(acrylic acid) macrochelates (GP) were then loaded to construct HEM@HMZN@GP for dual-source H 2 O 2 surge-driven tumor ferroptosis therapy. In acidic tumor microenvironment, Zn 2+ , H 2 O 2 , HEM, and GP can be released from HEM@HMZN@GP. The released Zn 2+ damages mitochondrial electron transport chain (ETC) and generates superoxide anions (•O 2 − ), which can be rapidly catalyzed by superoxide dismutase into H 2 O 2 . The dual-source of H 2 O 2 markedly elevates local oxidative stress. HEM can be enzymatically converted by heme oxygenase‑1 to Fe 2+ , which reacts with the abundant H 2 O 2 via Fenton reaction to produce hydroxyl radicals, initiating lipid peroxidation and ferroptosis. GP enhances T 1 ‑weighted magnetic resonance imaging signals, facilitating drug delivery visualization in tumors.
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Translational Cancer Research
·
2026
·Vol. 15
·期 7
·555
·
IF 2.1
Junjie Wu,Congxing Liu,Yaya Sun,Guangqing Jiang,Yupeng Zhao,Yihong Zhang,Yiping Yin,Xin Shi
Background Colon cancer (CC) is a heterogeneous disease with increasing morbidity and mortality. Ferroptosis, a recently identified form of regulated cell death (RCD) characterized by the massive accumulation of iron-dependent lipid peroxidation (LPO), has been proven to be closely associated with various biological behaviors of CC. Moreover, accumulating evidence reveals that ALOX12 is essential for p53-mediated ferroptosis through distinct pathways. Therefore, our study aims to explore the specific mechanisms by which ALOX12 regulates tumorigenesis in CC through ferroptosis pathway. Methods We explored the characteristics of ALOX12 expression and its correlation with prognosis in CC patients and cell lines, followed by a series of functional assays in vitro and in vivo to investigate the mechanisms underlying the functions of ALOX12 in p53-driven ferroptosis. Results We discovered that ALOX12 was downregulated in CC tissues and cell lines, which was correlated with poor prognosis. Furthermore, overexpression of ALOX12 suppressed cell proliferation and tumorigenesis by upregulating reactive oxygen species (ROS)-induced stress. We continuously found that increased ALOX12 levels enhanced the sensitivity of CC cells to a distinct ferroptosis, which required both p53 activation and additional ROS, and differed from that induced by erastin. Conclusions Our study demonstrates the oncosuppressive behavior of ALOX12 in CC. Mechanistically, we discover that p53 can indirectly activate ALOX12 function by suppressing its transcriptional target SLC7A11, resulting in an ALOX12-dependent ferroptotic pathway. Targeting ALOX12 may provide a novel biomarker or new therapeutic strategies for improving the prognosis of CC.
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Materials Today Bio
·
2026
·
IF 11
Pan Zhang,Minglun Liu,Lei Huang,Zijie Zhao,Qianqian Zhang,Yunhao Li,Yuncong Chen,Lili Liang
Triple-negative breast cancer (TNBC) frequently exhibits profound chemoresistance and a highly immunosuppressive tumor microenvironment (TME), leading to suboptimal clinical outcomes with high risks of early recurrence and distant metastasis. Existing monotherapies remain inadequate in disrupting these therapeutic barriers. To overcome the aforementioned obstacles, we developed a spatiotemporally regulated organelle-targeted nanoplatform, IR820-GEM@MIL101 (IGM), Its design aims to achieve precise mitochondrial intervention and coordinate cGAS–STING-mediated immune activation. This design relies on EPR-mediated passive targeting to achieve preferential tumor accumulation, allowing IGM to accumulate specifically in tumor tissues and trigger a series of reactions in response to endogenous stimuli (acidic pH and elevated glutathione) in synergy with exogenous near-infrared laser activation, enabling controlled drug release. The platform efficiently eliminates tumor cells by inducing multiple modes of cell death, including pyroptosis, ferroptosis, and apoptosis, while simultaneously triggering immunogenic cell death (ICD) and activating the cGAS–STING pathway. This dual immunostimulatory strategy effectively converts “cold” tumors into “hot” tumors. In a bilateral tumor model, IGM treatment increased CD8 + T-cell infiltration in distal tumors by 94% and achieved a tumor inhibition rate of 92.7% in distant lesions. This work shifts the therapeutic focus from superficial multi-drug packaging to precise organelle-targeted intervention, providing a promising strategy for light-regulated combinatorial immunotherapy against aggressive malignancies.
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Translational Cancer Research
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2026
·Vol. 15
·期 3
·179
·
IF 2.1
Jia-Yi Lu,Xin-Miao Zhao,Xian-Bao Liu,Li Gao
Background Oral squamous cell carcinoma (OSCC) is the most common oral malignancy, affecting the tongue, palate, mouth floor, alveolar ridge, and buccal mucosa. Kaempferol, a natural flavonoid, exhibits anti-oral cancer properties, but its mechanisms remain unclear. This study aimed to investigate kaempferol’s therapeutic potential and molecular mechanisms in OSCC using network pharmacology, molecular docking, and experimental validation. Methods Kaempferol’s components and targets were identified via the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). OSCC-related genes were sourced from GeneCards and Gene Expression Omnibus (GEO) databases. Network and molecular docking analyses were performed using Cytoscape and Autodock, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using Database for Annotation, Visualization and Integrated Discovery (DAVID). In vitro and in vivo experiments validated kaempferol’s effects. Results Kaempferol induced ferroptosis, reducing OSCC cell viability and increasing apoptosis dose-dependently. Carbonic anhydrase IX (CA9) emerged as a core gene mediating kaempferol’s anti-OSCC effects via ferroptosis. Molecular docking confirmed strong binding affinity between kaempferol and CA9 (−6.24 kcal/mol). GO and KEGG analyses revealed kaempferol’s modulation of p53/FoxO/cellular senescence pathways. Experiments confirmed kaempferol’s inhibition of OSCC proliferation and migration through CA9/ferroptosis induction. Conclusions Kaempferol exerts anti-OSCC effects via CA9/ferroptosis, highlighting its potential as a therapeutic agent for OSCC.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2026
·
IF 6
Wanmei Zhou,Zixin Wang,Chengdong Nie,Haiting Tian,Xiaoyi Duan,Lina Fu,Quan Zhou,Litao Wang,Yujie Fu
Triple-negative breast cancer (TNBC) lacks effective tumor-selective strategies, particularly limiting ferroptosis-based therapies that depend on oxidative stress. Here, we develop a structurally reinforced ternary redox-cycling nanoreactor that integrates Zr 4 ⁺-stabilized zeolitic imidazolate framework-8 (ZIF-8) with redox-active Cu/Mn centers and ultrasmall Au nanodots, while co-loading paclitaxel (PTX) for acidic tumor microenvironment-responsive release. The Cu-Mn-Au interfaces enable rapid electron shuttling, sustaining multivalent metal cycling, accelerating Fenton-like reactive oxygen species (ROS) generation, depleting GSH, and promoting lipid peroxidation. Density functional theory (DFT) calculations further support its self-perpetuating redox mechanism. Dual surface modification with 4 T1 cell membranes and folic acid confers homotypic and receptor-mediated targeting. Mechanistic studies reveal coordinated GPX4/SLC7A11 suppression, PTX-enhanced cell-cycle arrest, and NCOA4/HO-1-mediated ferritinophagy, collectively amplifying ferroptosis. Unlike conventional metal–organic frameworks (MOFs), this Zr-reinforced trimetallic system maintains continuous redox cycling under reductive conditions. Overall, the nanoreactor achieves sustained ROS amplification, iron-homeostasis remodeling, and enhanced tumor-selective ferroptosis, offering a promising therapeutic strategy for TNBC. Download: Download high-res image (197KB) Download: Download full-size image
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TOXICOLOGY
·
2026
·
IF 5.2
Yu Wang,Xu Han,Zizheng Wang,Yushan Song,Yiqiang Zhang,Mingwei Xing,Hongjing Zhao
Arsenic (As) is a widespread environmental toxicant that poses severe threats to animal and human health by disrupting multiple cellular processes. In this study, embryonic zebrafish fibroblast cells (ZF4) were used as an in vitro model to investigate the role of Alox12-mediated lipoxygenation in arsenite-induced ferroptosis. Transcriptomic analysis revealed that arsenite exposure (20 μM, 24–48 h) globally induced oxidative stress, apoptosis, cell cycle arrest, and autophagic cell death in a time-dependent manner. Notably, ferroptosis was absent at the early stage but became prominent upon prolonged exposure, coinciding with increased Alox12 expression and 12-HETE production. Overexpression of Alox12 under arsenite stress significantly elevated lipid peroxidation, ROS accumulation, and cell death, whereas siRNA-mediated knockdown of Alox12 partially rescued these phenotypes and restored GPx4 activity. These findings demonstrate that Alox12 mediates the transition from ferroptosis suppression to activation during arsenite toxicity, presenting a checkpoint-like phenotypic phenomenon. This work provides mechanistic insight into arsenism and a potential molecular target for ferroptosis-based therapeutic intervention.
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Advanced Healthcare Materials
·
2026
·
IF 11
Ling Wang,Haiping Zhong,Hui Zhang,Rongjie Wei,Maoyu Cai,Liangpin Li,Xueyan Zhou,Xia Hua,Shutao Guo,Xiaoyong Yuan
Fungal keratitis is a major cause of corneal blindness and remains difficult to treat due to poor drug retention, frequent dosing, and inadequate modulation of pathogenic mechanisms. Current therapies largely focus on antifungal efficacy while neglecting inflammation-, fibrosis-, and cell death–related pathways. Here, ferroptosis is identified as a critical pathogenic target, and a synergistic therapeutic strategy is developed using a thermosensitive in situ-forming hydrogel composed of poloxamer and hyaluronic acid, enabling the co-delivery of a ferroptosis inhibitor (ferrostatin-1, Fer-1) and the antifungal agent (voriconazole, VOR), termed PX/HA/Fer-1/VOR hydrogel. Upon administration, the hydrogel exhibits lens-like adhesion to corneal defects, forming a localized drug reservoir that significantly enhances corneal retention and prolongs drug residence time by at least 90 min. In vitro studies demonstrate enhanced antifungal activity, while in vivo fungal keratitis models show superior therapeutic efficacy compared with conventional voriconazole eye drops administered six times daily. Notably, a single daily application effectively suppresses inflammation, reduces corneal fibrosis and scarring, and promotes recovery of visual function. Mechanistically, the composite hydrogel exerts synergistic effects through zinc ion chelation–mediated antifungal activity, inhibition of ferroptosis, and attenuation of fibrosis. This multifunctional hydrogel platform offers a promising therapeutic strategy for fungal keratitis.
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高影响因子
INFLAMMATION RESEARCH
·
2026
·Vol. 75
·期 1
·37
·
IF 6.2
Wang Rui,Zou Ziwei,An Yi,Wang Liulin,Li Chengyin,Zou Yinshui,Wang Guangzhi
Background Acute kidney injury (AKI), characterized by rapid renal dysfunction and high mortality, is critically driven by ferroptosis, an iron-dependent form of cell death. While PTEN-induced kinase 1 (PINK1) and sirtuin 3 (SIRT3) are implicated in mitochondrial homeostasis and ferroptosis regulation, their mechanistic interplay in AKI remains unclear. This study investigated the role of emodin, a natural anthraquinone, in alleviating AKI via SIRT3-mediated PINK1 deacetylation and ferroptosis suppression, focusing on mitochondrial integrity, transferrin (TF) interaction, and redox balance. Materials and methods Male C57BL/6 mice ( n = 6/group), PINK1⁻/⁻, and SIRT3⁻/⁻ mice were pretreated with emodin (40–160 mg/kg, 3 days) before LPS-induced AKI (15 mg/kg). Human renal tubular HK-2 cells were treated with emodin (10–40 µg/ml) and Erastin (0.4 µM, 24 h). Assays included RNA sequencing, immunoprecipitation-mass spectrometry (IP-MS), histopathology (H&E/PAS/PB-DAB staining), ROS/Fe²⁺/GSH quantification, and immunoblotting. Statistical analysis used ANOVA and Student’s t-test. Results Emodin reduced serum creatinine and urea in AKI mice, alongside decreased tubular injury and apoptosis. RNA-seq identified ferroptosis as the central pathway, with emodin upregulating PINK1 expression. IP-MS revealed emodin disrupted PINK1-TF binding via SIRT3-mediated deacetylation, reducing Fe²⁺ accumulation and restoring GPX4 levels. In SIRT3⁻/⁻ and PINK1⁻/⁻ models, emodin’s protective effects were abolished, confirming pathway dependency. Conclusion Emodin mitigates AKI by activating the SIRT3/PINK1 axis, suppressing ferroptosis through cytoplasmic PINK1 deacetylation and TF interaction disruption. These findings highlight SIRT3/PINK1 as a therapeutic target and emodin as a potential agent for AKI management.
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