BIOMATERIALS
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2026
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IF 13.6
Jinwu Wang,Chao Lou,Zhihao Shen,Jin Yang,Hongyi Jiang,Heng Yu,Yu Zhang,Yangbo Li,Hua Chen,Aimin Wu,Zengjie Zhang,Leyi Cai,Wenhao Zheng
Osteoarthritis (OA) progression is driven by persistent oxidative stress and ferroptosis, which erode chondrocyte viability and extracellular matrix integrity. Although mesenchymal stem cell–derived exosomes (MSC-EXO) hold regenerative promise, their native cargo lacks the adaptability to withstand such a hostile microenvironment, limiting therapeutic efficacy. Here, we demonstrated a synergistic strategy involving reverse-adaptation and engineered MSC exosomes against ferroptosis in osteoarthritis. Firstly, the reverse-adaptation strategy in which OA-like oxidative stress was harnessed to precondition MSCs, thereby identifying miR-142a-3p as a key therapeutic mediator in tert -butyl hydroperoxide (TBHP)-modified exosomes (T-EXO). Subsequently, we engineered MSC-derived exosomes via miR-142a-3p electroporation (EXO miR−142a−3p ) with unique anti-ferroptosis and antioxidative properties. EXO miR−142a−3p were markedly enriched with miR-142a-3p, which directly targeted the GSK3β/Nrf2/SLC7A11 axis to suppress ferroptosis and reactive oxygen species (ROS) accumulation. Compared to naive EXO, EXO miR−142a−3p exhibited superior protection against cartilage matrix degradation and significantly slowed OA progression in a murine model. By integrating these engineered exosomes into a biodegradable, cartilage-targeted, and lubricious microsphere platform, we achieved sustained, site-specific delivery that amplified therapeutic durability and efficacy. This platform robustly mitigated extracellular matrix (ECM) degradation, ferroptosis, and oxidative stress in vitro, and conferred significant cartilage protection in a destabilization of medial meniscus (DMM)-induced OA model via efficient, prolonged intra-articular release. Collectively, this innovative approach not only provides potent cartilage protection in preclinical models but also establishes a paradigm for precision, microenvironment-adaptive regenerative therapies for OA and other degenerative diseases.
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Materials Today Bio
·
2026
·
IF 11
Mengen Guo,Wenjie Xu,Yanjin Peng,Yucheng Tang,Xinyan Hao,Tiantian Tang,Xinying Liu,Hai Huang,Ruyue Han,Junyong Wu,Daxiong Xiang
Bacterial combination therapy offers immense promise for treating aggressive "cold" solid tumors, such as triple-negative breast cancer (TNBC). However, the clinical translatability of traditional genetic engineering is often hampered by operational complexity and genetic instability. Here, we developed A-SPB—a non-genetically engineered, multi-functional living bioreactor based on Shewanella oneidensis MR-1 (SO), surface-modified with Prussian blue (PB) nanoparticles and attenuated via deoxycholic acid (DA) treatment. This platform serves as an in situ metabolic factory that "hijacks" the sulfur-metabolism within the hypoxic tumor microenvironment. By actively depleting cysteine, A-SPB not only starves the glutathione (GSH) synthesis pathway but also generates hydrogen sulfide (H 2 S) to inhibit the transsulfuration bypass, leading to a dual-pronged collapse of the GSH/GPX4 antioxidant axis and triggering robust tumor ferroptosis. This metabolic sensitization is further amplified by the PB-mediated photothermal therapy (PTT), which generates localized hyperthermia and excessive reactive oxygen species (ROS). Notably, the PTT serves as a dual-functional "bio-switch": it promotes acute tumor ablation while simultaneously triggering bacterial self-lysis to ensure biosafety. This programmed lysis releases a synergistic cocktail of bacterial PAMPs and tumor-derived DAMPs, which effectively remodels the immunosuppressive TME and initiates a potent systemic antitumor immune response. By integrating metabolic reprogramming, sensitized ferroptosis, and on-demand immune activation through simple surface engineering, this study provides a highly translatable and safe paradigm for the next generation of living bacterial therapeutics.
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PHYTOMEDICINE
·
2026
·
IF 8.3
Hongjin Wang,Jingjing Li,Xiaogang Xu,Yixi Zeng,Guofeng Shi,Lanyue Zhang,Junxia Zheng,Hui Li
Background Skin photo-aging induced by ultraviolet radiation (UVR) leads to aesthetic alterations, structural degradation, and loss of barrier function. Ferroptosis has been implicated upon UVR stress but the driving modifiers remain largely undefined. Naringin has been reported to exert protective effects against UVR damage, however, the underlying mechanisms remain incompletely understood. Purpose To explore the driving factors of UVR-induced ferroptosis and to comprehensively evaluate the effects and underlying mechanisms of naringin in repressing UVR-induced photo-aging. Methods A mouse model in which the dorsal skin, as well as a cell model using HaCaT keratinocytes, were exposed to UVR to simulate daily sun exposure. Lentivirus-mediated knockdown, ChIP-seq, and RNA-seq analysis were used to evaluate the role of NR4A1 in UVR-induced ferroptosis. RNA-seq and metabonomics were performed to elucidate the underlying mechanisms of naringin against photo-aging. Molecular dynamics simulations/DARTS/CETSA, and co-IP assays were employed to investigate the mechanism by which naringin regulates NR4A1 expression. Results Reduction of NR4A1 leads to excessive lipid metabolism and initiates ferroptosis in UVR-induced photo-aging. Naringin directly binds to NR4A1, enhancing its stability by preventing ubiquitin-mediated degradation, transcriptionally represses EGR1 and LDLR expression, thereby suppressing lipid peroxidation and ferroptotic damage. Remarkably, both genetic deficiency and pharmacological inhibition of NR4A1 across diverse models abolish the effects of naringin against photo-aging. Conclusion Our findings emphasize the critical role of NR4A1 in ferroptosis driven by dysregulated lipid metabolism and reveal the therapeutic potential of targeting NR4A1 with naringin in UVR-induced photo-aging, as well as in the other relevant lipid metabolism dysfunction disorders.
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TOXICOLOGY
·
2026
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IF 4.6
Jin Chen,Hanwen Hu,Jing Fu,Yaolin He,Hui Zhou,Jingwei Lei,Ming Huang,Jianqi Wang,Anfei Liu,Zhenzhong Liu
Trimethyltin chloride (TMT), a pervasive environmental organic tin pollutant, has been implicated in cardiac injury, though its underlying mechanisms remain unclear. TMT exposure triggers excessive reactive oxygen species (ROS) generation, a key inducer of ferroptosis—a regulated form of cell death driven by iron-dependent lipid peroxidation. NADPH oxidase 4 (NOX4), highly expressed during cardiac development, plays a critical role in myocardial ROS production, while the Keap1/Nrf2 pathway regulates cellular ROS homeostasis. We hypothesized that TMT induces cardiac developmental defects by activating NOX4/Keap1/ROS-mediated ferroptosis. TMT exposure induced cardiac malformations, pericardial edema, and reduced heart rate in zebrafish embryos. Further studies revealed that TMT upregulated nox4 expression in embryonic hearts. Notably, pharmacological inhibition or genetic knockdown of nox4 markedly attenuated TMT-induced cardiac defects. Moreover, nox4 suppression antagonized TMT-triggered dysregulation of the Keap1/Nrf2 axis, ROS overaccumulation, mitochondrial damage, and ferroptosis-related abnormalities—including Fe²⁺ accumulation, elevated lipid peroxidation, and downregulated glutathione peroxidase 4 (GPX4) expression. Crucially, inhibition or knockdown of keap1 similarly mitigated TMT-induced ROS bursts, mitochondrial injury, and ferroptosis progression. Intervention with ferroptosis-specific inhibitors (Liproxstatin-1 and Myricetin) confirmed that ferroptosis directly contributes to TMT-induced cardiac developmental defects. This study demonstrates that TMT induces cardiac malformations by activating ferroptosis via the nox4/Keap1/Nrf2/ROS signaling axis. These findings reveal a novel mechanism underlying TMT cardiotoxicity, provide theoretical insights for assessing TMT exposure as a risk factor for congenital heart disease, and identify potential molecular targets for therapeutic intervention.
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BIOMATERIALS
·
2023
·
IF 14
Qingya Wang,Jian He,Yuchen Qi,Yang Ye,Juan Ye,Min Zhou
Uveal melanoma is the most common primary ocular tumor owing to its highly invasive and metastatic characteristics. Currently, standard clinical treatment has an unsatisfied curative effect due to the lack of an effective approach to inhibit the tumor metastasis. Therefore, it is necessary to develop a new strategy that can both restraint local tumors and suppress the ocular tumor metastasis. Herein, we developed ultrasound-responsive nanoparticles (FeP NPs) that can both hinder the growth of in situ ocular tumor and prevent the tumor metastasis through the ferroptosis-apoptosis combined-anticancer strategy. The FeP NPs were assembling by stimulating gallic acid-Fe (III) and paclitaxel , then could be internalized into tumor cells under the cooperative effect of ultrasound, which further activates the intracellular Fenton reaction and generates high reactive oxygen species levels, ultimately leading to mitochondrial damage, lipid per-oxidation, and apoptosis. The FeP NPs can efficiently inhibit the tumor growth in an orthotopic uveal melanoma model. More importantly, the level of the promoting-metastatic factor nerve growth factor receptor (NGFR) secreted by cancer cells is significantly reduced, further limits cancer metastasis to the cervical lymph node and finally inhibits lung metastasis of uveal melanoma. We believe that these designed ultrasound-enhanced nanoparticles possess potential clinical application for preventing the regeneration and metastasis of uveal melanoma.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.2
Jia-Gen Cui,Hao Zhang,Ming-Shan Chen,Jia-Xin Wang,Xue-Nan Li,Jin-Long Li
Lycopene (LYC), a natural antioxidant compound abundant in tomatoes, has established neuroprotective roles due to its antioxidant and anti-inflammatory properties. Di (2-ethylhexyl) phthalate (DEHP), a common plasticizer, is known to exert neurotoxic effects. However, the mechanisms of DEHP-induced neurotoxicity remain unclear. Furthermore, effective preventive strategies against this neurotoxicity are still lacking. This study, employing in vitro (BV2 cells) and in vivo (ICR mouse) models, demonstrates that LYC prevents DEHP-induced cerebellar damage by suppressing the triggering of dose-dependent microglial ferroptosis and neuroinflammation. Mechanistically, LYC inhibited the phosphatidylethanolamine-binding protein 1 (PEBP1)/arachidonate 15-lipoxygenase (ALOX15) axis (supported by immunofluorescence and Western blot assays), leading to reduced reactive oxygen species by approximately 48% in the cerebellum, which ultimately prevented neuroinflammation. Our findings reveal that LYC prevents DEHP-induced neurotoxicity by inhibiting microglial ferroptosis via the PEBP1/ALOX15 axis. Furthermore, our findings highlight the clinical promise of LYC as a novel neuroprotective treatment against environmental toxicant-induced damage.
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JOURNAL OF MATERIALS SCIENCE
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2026
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IF 3.9
Wang Rong,Tian Xiao-Li,Li Jin,Chen Jia-Jia,Hu Yue,Zhang Ji
Ferroptosis is a non-apoptotic form of cell death that offers unique advantages in various cancer therapies. Gene therapy, on the other hand, involves transferring therapeutic genes into cancer cells to regulate related proteins and exert therapeutic effects. Nanomaterials that combine the ability to induce ferroptosis in cancer cells with gene delivery functionality hold great potential for tumor therapy. Herein, we designed and synthesized a series of ferrocene-containing (Fc) cationic lipids (NFC-1~4) based on the Ugi reaction. Fc, as a typical Fenton reaction catalyst, can effectively trigger ferroptosis in cancer cells. The results showed that NFC-1~3 lipoplexes could be efficiently taken up by A549 cells and exhibit excellent gene transfection capabilities, with the best transfection efficiency surpassing that of Lipofectamine 2000. Reactive oxygen species (ROS) detection experiments revealed that NFC-2 possesses Fenton characteristics, enabling it to induce the Fenton reaction and produce ROS. In vitro antitumor experiments demonstrated that NFC-2 LNPs could inhibit tumor cell growth to some extent, with its efficacy significantly enhanced after DNA encapsulation. Mechanistic studies indicated that the Fenton reaction mediated by NFC-2@DNA lipoplexes converted endogenous H 2 O 2 into highly toxic ·OH, leading to increased intracellular ROS levels, glutathione (GSH) depletion, and inactivation of glutathione peroxidase 4 (GPX4). The disruption of the cellular redox balance caused excessive accumulation of lipid peroxides (LPOs), ultimately inducing ferroptosis. NFC-2 holds promise as an efficient ferroptosis agent and a dual-function lipid for co-delivering DNA, offering potential for combined gene therapy and ferroptosis-based cancer treatment. Graphical abstract
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CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.4
Yuankun Zhou,Jiajun Guo,Xiaoyan Feng,Hengyi Xu
Nanoplastics (NPs) and chromium (Cr) are ubiquitous in the environment, causing severe pollution and posing significant potential threats to human health. Polylactic acid (PLA) and Cr are among widely used bioplastic and heavy metal, respectively, both capable of contaminating water sources through corresponding pathways and posing substantial risks to human health. Nanoplastics can act as carriers for heavy metals, thereby enhancing their bioaccumulation and toxicity. Therefore, this study investigated the effects of combined exposure to Cr(VI) and PLA NPs on mice kidneys and its potential mechanisms. Results indicated that exposure to PLA NPs alone did not exhibit significant toxic effects on the kidneys. However, combined exposure to Cr(VI) and PLA NPs caused severe kidney damage in mice. This indirectly suggests that Cr(VI) and PLA NPs exhibit synergistic toxicity rather than simple additive effects. Furthermore, combined exposure exacerbated the toxic mechanism by inducing mitochondrial damage and excessive reactive oxygen species (ROS) production, thereby triggering mitophagy. Overactivated mitophagy exacerbated lipid peroxidation by releasing free iron, thereby amplifying ROS-mediated ferroptosis. This study investigates the synergistic renal toxicity of Cr(VI) and PLA NPs, providing scientific evidence for the combined toxicity mechanism of exposure to MNPs and heavy metals.
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BIOMATERIALS
·
2026
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IF 13.6
Qin Ouyang,Runwei Gao,Sisi Li,Junhao Liang,Pei Li,Wenhu Zhou
Oral mucositis (OM) is a common inflammatory disorder characterized by epithelial barrier destruction, uncontrolled inflammation, and impaired mucosal repair. Despite the complex tissue microenvironment in OM, which is driven by interconnected pathological processes, current therapeutic approaches are hindered by their predominant focus on single factors. In this study, we identified ferroptosis as a key driver of OM progression through clinical sample analysis and mechanistic validation, revealing that disrupted selenium metabolism and decreased Glutathione Peroxidase 4 (GPX4) expression promote lipid peroxidation and epithelial cell death. To address this, we developed a poly(5-hydroxytryptamine)-functionalized selenium nanoparticle system (PST-SeNPs) that integrates mucosal adhesion, antioxidation, and immunoregulation capabilities. The PST-SeNPs exhibited strong mucosal adhesion and deep tissue penetration in oral ulcer regions. Mechanistically, the system synchronously inhibited ferroptosis by restoring GPX4 activity, alleviating oxidative stress, and modulating macrophage polarization toward an anti-inflammatory phenotype, thereby reconstructing the epithelial and immune microenvironments. In vitro and in vivo studies demonstrated that PST-SeNPs effectively reversed the pathological cycle of “oxidative stress–ferroptosis–inflammation,” accelerated mucosal healing, and significantly improved therapeutic outcomes compared to conventional selenium formulations. This work establishes the pivotal role of selenium metabolism imbalance and ferroptosis in OM progression and proposes an integrated nanoplatform that synergistically targets epithelial and immune microenvironments.
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JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
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2026
·Vol. 40
·期 7
·e70982
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IF 3.6
Zimeng Liu,Yunpeng Gao,Musen Li,Qingsong Sun,Yunhe Fu,Yue Zhang
Mastitis is a prevalent gynecological disorder in women, with Staphylococcus aureus ( S. aureus ) serving as a primary etiological pathogen of this condition. Cryptotanshinone (CPT) has been demonstrated to exert anti-oxidative stress and anti-inflammatory effects, conferring therapeutic benefits for a diverse range of inflammatory diseases. However, its efficacy and underlying regulatory mechanisms in ameliorating S. aureus -induced mastitis remain elusive. Therefore, the present study was designed to elucidate the protective effects and molecular regulatory mechanisms of CPT against S. aureus -induced mastitis. A murine model of S. aureus -induced mastitis was established via intramammary injection of S. aureus , and CPT was administered to the model mice for therapeutic intervention. In vivo experiments revealed that CPT administration mitigated S. aureus -induced mastitis in mice by suppressing the production of pro-inflammatory cytokines and inhibiting ferroptosis. In vitro, CPT abrogated the S. aureus -induced elevation of TNF-α, IL-1β, MDA, ROS, and Fe 2+ levels in mouse mammary epithelial cells (MMECs); additionally, it restored the ATP and GSH levels that were reduced by S. aureus stimulation in these cells. Furthermore, CPT concentration-dependently upregulated the expression of GPX4, Nrf2 and HO-1 in MMECs. Notably, the inhibitory effects of CPT on S. aureus -induced inflammatory responses and ferroptosis were abrogated in Nrf2-knockdown MMECs. In conclusion, this study demonstrates that CPT exerts a robust protective effect against S. aureus -induced mastitis by suppressing inflammatory responses and inhibiting ferroptosis through the activation of the Nrf2/GPX4 signaling pathway.
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Frontiers in Pharmacology
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2026
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IF 5.4
Chen Bao,Decai Wang,Chao Liu,Meizhou Zhang,Qian Liu,Jiannan Hu,Yuzhou Wu,Shuyun Xu
Ferroptosis is an iron-dependent programmed cell death mechanism triggered by the accumulation of lipid-based reactive oxygen species (ROS). It is closely implicated in the pathogenesis of asthma. Liproxstatin-1 (LIP-1) is a ferroptosis inhibitor that is beneficial for treating neutrophilic asthma. However, low water solubility, limited blood concentration, and poor mucus permeability and biocompatibility limit the therapeutic efficacy of LIP-1. In this study, we successfully constructed polydopamine–polyethylene glycol–LIP-1 nanoparticles (PDA-PEG-LIP-1 NPs) for the treatment of neutrophilic asthma. Inhalation of PDA-PEG-LIP-1 NPs effectively inhibited lipopolysaccharide (LPS)- and interleukin (IL)-13-induced ferroptosis by alleviating lipid peroxidation and ROS production and chelating free ferrous ions (Fe 2+ ). In addition, results from asthma mouse models demonstrated that inhalation of PDA-PEG-LIP-1 NPs could overcome the limitations of LIP-1 and effectively inhibit ferroptosis. This research suggests that PDA-PEG-LIP-1 NPs are an effective, practical, and safe option for treating neutrophilic asthma.
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
·
2026
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IF 5
Qi Lou,Rui Bai,Yongwu Liu,Bo Li,Haoran Zhu,Guangzhong Liu
Reports indicate that MARCHF6 can regulate ferroptosis. • The high expression of MARCHF6 alleviates myocardial ischemia-reperfusion injury. • Elevated MARCHF6 expression inhibits ferroptosis in CMECs. • MARCHF6 regulates ferroptosis through the ADAMTS4/SDC-1 pathway. • MARCHF6 is a promising therapeutic target for MIRI. Myocardial ischemia-reperfusion injury is a key factor affecting prognosis after acute myocardial infarction. MARCHF6, as an E3 ubiquitin ligase, is closely implicated in the ferroptosis process. The role of MARCHF6 in MIRI and its mechanism for regulating myocardial cell ferroptosis remained unclear. A mouse model of MIRI overexpressing MARCHF6 was established by tail vein injection of MARCHF6-overexpressing AAV9 virus, followed by left anterior descending coronary artery ligation surgery in mice. High expression of MARCHF6 significantly improved cardiac function and reduced myocardial injury in MIRI mice. Compared with the MIRI mice, the MARCHF6 overexpression mice exhibited a reduction of approximately 14% in myocardial infarction area. Histological damage in the cardiac ischemic penumbra region was markedly alleviated, and the number of cell deaths was significantly decreased. Concurrently, MARCHF6 overexpression substantially reduced serum levels of myocardial injury markers CK-MB, cTnI, and LDH. Mitochondrial morphological alterations and expression of ferroptosis-related indicators in the ischemic penumbra of the heart indicated that MARCHF6 overexpression alleviated ferroptosis in MIRI hearts. In an OGD/R-induced cardiomyocyte microvascular endothelial cell (CMEC) model, MARCHF6 overexpression alleviated lipid peroxidation and inhibited ferroptosis. MARCHF6 overexpression suppressed the upregulation of ACSL4 and 4-HNE while blocking the downregulation of SLC7A11 and GPX4 in vivo and vitro . Mechanistically, MARCHF6 promoted the ubiquitin-mediated degradation of ADAMTS4, thereby upregulating its downstream target SDC-1. This sequence of events inhibits lipid peroxidation, mitigates mitochondrial damage, and ultimately blocks the ferroptosis process in endothelial cells. These findings unveil a novel regulatory pathway involving MARCHF6/ADAMTS4/SDC-1 against MIRI by inhibiting ferroptosis. Download: Download high-res image (104KB) Download: Download full-size image
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