FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Wenjie Dai,Bo Xu,Liyang Ding,Zhen Zhang,Hong Yang,Tiantian He,Ling Liu,Xiuying Pei,Xufeng Fu
Primary ovarian insufficiency (POI) in younger women (under 40) manifests as irregular periods, high follicle-stimulating hormone (FSH), and low estradiol (E2), often triggered by chemotherapy. Though mesenchymal stem cell (MSC) therapy shows promise in treating POI, its exact mechanism remains unclear. This study reveals that human umbilical cord-derived MSCs (hUC-MSCs) can protect ovarian granulosa cells (GCs) from cyclophosphamide (CTX)-induced ferroptosis, a form of cell death driven by iron accumulation. CTX, commonly used to induce POI animal model, triggered ferroptosis in GCs, while hUC-MSCs treatment mitigated this effect, both in vivo and in vitro . Further investigations using ferroptosis and autophagy inhibitors suggest that hUC-MSCs act by suppressing ferroptosis in GCs. Interestingly, hUC-MSCs activate a protective antioxidant pathway in GCs via NRF2, a stress-response regulator. Overall, our findings suggest that hUC-MSCs improve ovarian function in CTX-induced POI by reducing ferroptosis in GCs. This study not only clarifies the mechanism behind the benefits of hUC-MSCs but also strengthens the case for their clinical use in treating POI. Additionally, it opens up a new avenue for protecting ovaries from chemotherapy-induced damage by regulating ferroptosis.
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ACS Nano
·
2024
·
IF 15.8
Guiqi Ma,Xinyu Zhang,Kunlong Zhao,Shuxuan Zhang,Ke Ren,Mengyao Mu,Chenyu Wang,Ximing Wang,Hui Liu,Jian Dong,Xiao Sun
Rational structure design benefits the development of efficient nanoplatforms for tumor theranostic application. In this work, a multifunctional polydopamine (PDA)-coated manganese sulfide (MnS) nanocluster was prepared. The polyhydroxy structure of PDA enhanced the water interaction with pH-responsive MnS nanoclusters via hydrogen bonds. At pH 5.5 conditions, the spin–lattice relaxation rate of MnS nanoclusters dramatically increased from 5.76 to 19.33 mM–1·s–1 after the PDA coating, which can be beneficial for efficient tumor magnetic resonance imaging. In addition, PDA endowed MnS nanoclusters with excellent biocompatibility and good photothermal conversion efficiency, which can be used for efficient tumor photothermal therapy (PTT). Furthermore, MnS nanoclusters possess the ability to release H2S in the acidic tumor microenvironment, effectively inhibiting mitochondrial respiration and adenosine triphosphate production. As a result, the expression of heat shock protein was obviously reduced, which can reduce the resistance of tumor cells to photothermal stimulation and enhance the efficacy of PTT. The released Mn2+ also displayed efficient peroxidase and glutathione oxidase-like activity, effectively inducing tumor cell ferroptosis and apoptosis at the same time. Therefore, this nanoplatform could be a potential nanotheranostic for magnetic resonance contrast enhancement and synergistic ferroptosis–PTT of tumors.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
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IF 8.5
Wei Liu,Kangcheng Zhao,Feng Chen,Chenkai Cai,Tianyuan Jiang,Liying Zhu,Chunyang Yu,Fang Liu,Muyu Yu
Poorly-controlled blood glucose frequently develop in diabetic wounds and hydrogel has been reported of great performance for diabetic wound healing. Consequently, we prepared poly-N-acryloyl glycinamide (PNAGA) and introduced polyglutamic acid (γ-PGA), Fe 3+ , small extracellular vesicles (sEVs) into PNAGA to form a dual physical cross-linking supramolecular hydrogel system (PFF) for diabetic wound healing. In this study, we successfully synthesized the PFF hydrogel and extracted the sEVs that were incorporated into PPF as PPF/sEVs. In our research, we find that PFF hydrogel possessed continuous porous structure and, exceptional resilience, excellent extensibility and flexibility, closely mimicking the mechanical performance of human skin. Moreover, the PFF/sEVs hydrogel could release sEVs, playing a critical role in wound healing. Our results showed PFF/sEVs hydrogel improved the wound healing characterized by shorter wound closure time and enhanced blood vessel density in vivo. Also, sEVs counteracted the inhibitory effects of high glucose on proliferation, migration, tube differentiation, malondialdehyde (MDA) and glutathione (GSH) levels, which may attribute to the inhibition of ferroptosis by influencing free fatty acids (FFA) metabolism in vitro. Our findings indicated that the low-cost, biocompatible, and multifunctional bioactive PFF supramolecular hydrogel loaded with sEVs hold tremendous application potential as a clinical platform for diabetic wound healing.
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Stem Cells Translational Medicine
·
2025
·Vol. 14
·期 3
·
IF 4.9
Zhao Zhi-Meng,Ding Jia-Ming,Li Yu,Wang Da-Chuan,Kuang Ming-Jie
Glucocorticoid-induced osteoporosis (GIOP), the most common cause of secondary osteoporosis, is characterized by significant bone loss, decreased bone quality, and increased fracture risk. The current treatments for GIOP have several drawbacks. Exosomes are vital for cellular processes. However, very few studies have focused on using human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-EXOs) for GIOP treatment. In vitro and in vivo dexamethasone was used to evaluate the therapeutic effects of hUCMSC-EXOs on GIOP. CCK-8 and EdU assays were used to evaluate cell viability and proliferation, respectively. We conducted an alkaline phosphatase activity assay, alizarin red staining, Western blotting, and real-time PCR to detect the effect on osteogenesis. TMT-labeled quantitative proteomic and bioinformatic analyses were performed. Furthermore, we performed Western blotting, immunofluorescence, reactive oxygen species assays, and lipid peroxidation assays to investigate the regulatory mechanism by which hUCMSC-EXOs affect cell proliferation and osteogenic differentiation. The in vivo effects of hUCMSC-EXOs were evaluated using micro-CT, hematoxylin, and eosin staining, and immunohistochemical staining. We found that hUCMSC-EXOs reversed the inhibitory effects of glucocorticoids on human bone marrow stromal cell (hBMSC) proliferation and osteogenic differentiation and demonstrated that hUCMSC-EXOs reversed GIOP via the PI3K/AKT signaling pathway, inhibiting lipid peroxidation in vitro and in vivo. HUCMSC-EXOs promote hBMSC osteogenesis through the PI3K/AKT signaling pathway, inhibit ferroptosis, and have therapeutic potential for GIOP in mice.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Hong Yang,Liyang Ding,Bo Xu,Zhen Zhang,Wenjie Dai,Tiantian He,Ling Liu,Xing Du,Xufeng Fu
Di-(2-ethylhexyl)phthalate (DEHP) is a common plasticizer that has been shown to significantly negatively affect male reproductive health. On the other hand, Lycium barbarum polysaccharide (LBP) has been shown to improve reproductive function. Therefore, we hypothesized that LBP may ameliorate DEHP-induced male reproductive damage. Herein, we found that LBP could alleviate DEHP-induced testicular damage and sperm abnormalities. Furthermore, histomorphological analysis of mice testis revealed that LBP primarily ameliorated the DEHP-induced male reproductive damage by targeting Sertoli cells. Moreover, the detection of the function-related genes of Sertoli cells confirmed this finding. The serum of mice in the Control, DEHP, and DEHP+LBP groups was analyzed using non-targeted metabolomics to further elucidate the mechanism of action of LBP in improving DEHP-induced male reproductive damage. According to the results, the differential metabolites were mainly enriched in the glutamate metabolism pathway, implying that LBP may alleviate the ferroptosis-related DEHP-induced testicular injury. Related ferroptosis markers were also found in mice testis. These findings collectively suggest that LBP may ameliorate DEHP-induced testicular injury via alleviating ferroptosis in Sertoli cells. To clarify the specific mechanism, we constructed a cell model in vitro by treating TM4 cells (the Sertoli cell line) with LBP and MEHP (the in vivo DEHP metabolite). Our findings revealed that LBP can improve the function of DEHP-affected Sertoli cells. Furthermore, the analysis of lipid peroxidation, Fe 2+ content, and ferroptosis-related protein expressions demonstrated that LBP could ameliorate MEHP-induced ferroptosis in TM4 cells. To clarify the specific mechanism, glutamate metabolism-related proteins involved in the ferroptosis pathway were detected. According to the results, there were significant changes in the expression of NRF2, SLC7A11 and GPX4 proteins, which are involved in the ferroptosis glutamate metabolism pathway. Furthermore, supplementation of NRF2, SLC7A11, and GPX4 inhibitors (ML385, Erastin, and RSL3, respectively) blocked the therapeutic effect of LBP in alleviating MEHP-induced ferroptosis in TM4 cells, implying that LBP could also ameliorate MEHP-induced ferroptosis via the NRF2/SLC7A11/GPX4 pathway. In summary, these findings show that LBP can alleviate DEHP/MEHP-induced ferroptosis through the NRF2/SLC7A11/GPX4 pathway, ameliorating Sertoli cell dysfunction and improving the DEHP-induced male reproductive damage. Therefore, the clinical administration of LBP could be an effective strategy for preventing DEHP-induced male reproductive injury.
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高影响因子
BRAIN RESEARCH
·
2025
·
IF 2.6
Xingli Tan,Xiaoli Su,Ying Wang,Weiwei Liang,Di Wang,Di Huo,Hongyong Wang,Yan Qi,Wenmo Zhang,Ling Han,Dongmei Zhang,Ming Wang,Jing Xu,Shuyu Wang,Jing Wang,Honglin Feng
Dysregulation of copper and iron homeostasis contributes to the progression of amyotrophic lateral sclerosis (ALS), but the role and mechanism of COMM domain containing 4 (COMMD4) in ALS remains unclear. In this research, we showed that the expression of COMMD4 was upregulated in ALS cells and animal models. The increased COMMD4 induced neuronal ferroptosis by disrupting the Cu-Fe balance. Mechanistic studies indicated that COMMD4 inhibited ferroportin (FPN)-mediated neuronal iron efflux by inhibiting intracellular copper and hephaestin (HEPH). Our findings demonstrated that COMMD4 depletion exerts neuroprotective effects on ALS by increasing intracellular copper and activating HEPH/FPN pathway, rather than affecting the interaction between HEPH and FPN. Targeting COMMD4 and its downstream signaling pathways may offer potential therapeutic avenues for ALS.
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BMC Complementary Medicine and Therapies
·
2025
·Vol. 25
·期 1
·451
·
IF 3.4
Pan Sunfeng,Xiong Lie,Li Jiakun,Wang Zhenjun,Su Yujuan,Fang Gaofeng,Zhu Minda,Shi Hanqiang,Li Jiayan,Liu Zhaoyan,Han Chunmao,Shi Yanbo
Background Venous leg ulcer (VLU) is among the most severe clinical manifestations of chronic venous disease (CVD) and imposes substantial burdens on both patients and society. VLU pathogenesis is closely associated with the impairment of vascular endothelial cells. In this study, tissue samples from the patients’ s skins around wound at different stages of CVD were collected during operation and used to elucidate the involvement of ferroptosis in the pathogenesis of VLU. Also the potential mechanism through which Huoxue Shengji (HXSJ) decoction alleviates ferroptosis in human umbilical vein endothelial cells (HUVECs) was investigated. Methods During surgical procedure such as great saphenous vein high ligation and stripping surgery, matched skin tissues from the normal, hyperpigmentation (HPT), lipodermatosclerosis (LDS), and VLU regions were collected from 10 patients with VLU, and the levels of iron and glutathione peroxidase 4 (GPX4) were quantified to evaluate ferroptosis. In vitro, HUVECs were used to iron overload induction using exogenous 100 µM ferric ammonium citrate (FAC) or 100 µM hemin, or ferroptosis induction with 10 µM erastin, and treated with 10 µg/ml HXSJ decoction for 24 h. Subsequently, lipid peroxidation (LPO) damage, mitochondrial function, and key genes involved in ferroptosis were assessed. Results Iron deposition in the affected skin of patients with CVD gradually increased before progression to VLU and significantly decreased during the VLU stage. Moreover, GPX4 expression increased significantly in the HPT stage but was gradually suppressed with further deterioration of CVD. The in vitro results indicated that in both the iron overload and ferroptosis models, HXSJ decoction effectively upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), solute carrier family 7 member 11 (SLC7A11, xCT), and GPX4, which was accompanied by the inhibition of malondialdehyde and protein carbonylation production, the alleviation of ferrous ion accumulation, and the restoration of mitochondrial function. Conclusions This study demonstrated that iron accumulation-mediated inactivation of GPX4 serves as a crucial mechanism in VLU formation through ferroptosis induction. Notably, the therapeutic mechanism through which HXSJ decoction alleviates ferroptosis involves Nrf2/xCT/GPX4 pathway activation and a reduction in ferrous ion accumulation. These findings may provide novel insights into VLU pathogenesis and give possible reason for developing traditional Chinese medicine therapies targeting ferroptosis and VLUs. Graphical
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2026
·
IF 2.5
Mengya Cai,Weijian Chen,Chao Lu,Wenqiang Li,Yimin Lu,Ling Cheng,Meirong Guo,Yun Liang,Yuanmei He,Wengang Liu,Tao Jiang
Impaired infected wound healing is closely associated with mitochondrial dysfunction, and ferroptosis has emerged as a key mechanism connecting oxidative stress to mitochondrial damage. Baicalein holds potential for modulating this process, yet its application is constrained by poor bioavailability. Herein, a multifunctional nano-delivery system (Ba@Zn-MSN@CH) was rationally designed for infected wound treatment. Zinc-doped mesoporous silica nanoparticles (Zn-MSN) were synthesized to serve as a baicalein carrier. Carboxymethyl chitosan (CMCS) and dihydrocaffeic acid were covalently grafted onto the surface of the nanoparticles via silanization and amidation reactions, leading to the formation of a stable core-shell structure. The introduction of macromolecular coating was found to not only prolong drug release but also enhance antioxidant and antibacterial efficacy. What's more, Ba@Zn-MSN@CH effectively alleviated mitochondrial damage by inhibiting ferroptosis, thereby restoring cell proliferation, migration, and angiogenesis, and ultimately accelerating infected wound healing. Mechanistically, Ba@Zn-MSN@CH inhibited ferroptosis by inducing AMP-activated Protein Kinase α (AMPKα) phosphorylation in fibroblasts. AMPKα sustained the abundance of nuclear factor erythroid 2-related factor 2 (Nrf2), which subsequently suppressed lipid peroxidation and inhibited ferroptotic cell death through upregulation of downstream antioxidant factors. Collectively, these findings demonstrated that Ba@Zn-MSN@CH accelerated infected wound healing by inhibiting ferroptosis through activation of the AMPK/Nrf2 signaling pathway, highlighting the potential of baicalein-based nanotherapeutics as a promising strategy for infected wound management.
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ADVANCED FUNCTIONAL MATERIALS
·
2026
·
IF 19.9
Yukun Hu,Shutao Gao,Chuanhui Xun,Hongchuan Wang,Tao Xu,Weidong Liang,Liang Ma,Weibin Sheng
Spinal cord injury (SCI) involves oxidative stress, inflammation, and mitochondrial dysfunction that impair neural cell survival, while conventional therapies fail to sustainably improve the lesion microenvironment. Here, we developed a composite hydrogel patch (Mg-CDs/Exo@EW) by leveraging the enzyme-mimicking activity and coordination crosslinking ability of magnesium-doped carbon dots (Mg-CDs) to induce egg white gelation, with uniform incorporation of orange juice–derived exosomes (Exo). Orange peel-derived CDs displayed strong antioxidative nanozyme activity, which was further enhanced by magnesium ion doping to promote M2 macrophage polarization, axonal regeneration, and neural repair. Transcriptomic and Western blot analyses revealed that Mg-CDs activate the GPX4/ACSL4 pathway to suppress neuronal ferroptosis. Untargeted metabolomics showed that Exo are enriched in flavonoids and vitamin C with potent antioxidative and anti-inflammatory effects, while their negatively charged surface and adhesion molecules provide targeted delivery and enhanced repair efficacy. In vivo, Mg-CDs/Exo@EW effectively alleviated oxidative stress, regulated inflammation, reduced glial scar formation, and supported axonal regeneration, ultimately improving motor functional recovery. This multifunctional platform offers a promising therapeutic strategy for SCI.
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ENVIRONMENTAL POLLUTION
·
2026
·
IF 7.2
Li Ma,Shiyi Tan,Wei Wang,Xulei Zuo,Hao Gao,Yuepu Pu,Juan Zhang
Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a widely used organophosphate flame retardant that is ubiquitously detected in environmental matrices and human biological samples, raising concerns about its potential health risks. However, the mechanisms underlying TDCPP-induced hepatotoxicity remain incompletely understood. Here, we investigated the hepatic effects of TDCPP using an integrated in vivo–in vitro approach combining a mouse exposure model, human-derived 3D liver organoids, and network toxicology analysis. Sub-chronic oral exposure to TDCPP in mice induced evident liver injury, characterized by histopathological alterations, elevated serum aminotransferase activities, and hepatic triglyceride accumulation accompanied by systemic lipid metabolism disorders. TDCPP exposure also disrupted hepatic redox homeostasis, as evidenced by glutathione depletion, enhanced lipid peroxidation, and downregulation of glutathione peroxidase 4, a key suppressor of ferroptosis. Consistently, TDCPP exposure reduced cell viability, promoted lipid droplet accumulation, increased reactive oxygen species levels, and suppressed GPX4 expression in human 3D liver organoids, recapitulating the major pathological features observed in vivo. Network toxicology analysis identified peroxisome proliferator-activated receptor gamma (PPARG) as a central node potentially involved in TDCPP-induced hepatotoxicity and ferroptosis, which was further supported by molecular docking analysis. Experimental validation confirmed that TDCPP exposure significantly upregulated PPARG expression in both mouse liver tissues and liver organoids. Overall, these findings indicate that TDCPP induces hepatic injury and lipid metabolic disturbance in association with ferroptosis, potentially mediated through a PPARG–GPX4 regulatory axis, providing human-relevant mechanistic insight into the hepatotoxic risk of this environmental contaminant.
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MATERIALS & DESIGN
·
2026
·
IF 8.2
Ruilin Ding,Hai Lin,Yinying Wu,Xuyuan Dong,Yangwei Fan,Longxia Chen,Gaochen Lan,Yu Shi,Meichen Wang,Enxiao Li
Virus-mimetic hollow Gd-Fe nanocarriers enable co-delivery of cisplatin and TGF-βRI inhibitor for synergistic chemo-ferroptosis therapy. • The nanoparticle trigger iron-dependent cell death while blocking TGF-β signaling, synergistically suppressing tumor growth. • The nanoparticle overcomes resistance to immune checkpoint therapy by shifting the tumor microenvironment toward an immune-active state. Ovarian carcinoma remains poorly responsive to immune checkpoint blockade, partly because of a TGF-β-enriched and immunosuppressive tumor microenvironment. Here, we developed a virus-mimetic hollow Gd-Fe nanocarrier for the co-delivery of cisplatin (DDP) and the TGF-β receptor I inhibitor TGFβRI-IN-3 (IN-3), aiming to integrate chemotherapy, ferroptosis induction, and TGF-β pathway blockade into a single therapeutic platform. DDP/IN-3@Gd-Fe nanoparticles (NPs) were prepared using a hard-template strategy. Cellular uptake, cytotoxicity, apoptosis, and ferroptosis-associated biochemical changes were evaluated in SKOV3 cells. In tumor-bearing mice, biodistribution, T1-weighted MRI contrast, biosafety, and antitumor efficacy were further investigated. The prepared NPs exhibited uniform size, good stability, and high drug loading with sustained release. In vitro , DDP/IN-3@Gd-Fe NPs were effectively internalized by SKOV3 cells and demonstrated superior cytotoxicity, apoptosis induction, and ferroptosis promotion compared to free drugs. In vivo , DDP/IN-3@Gd-Fe NPs exhibited the strongest tumor growth inhibition, involving synergistic induction of apoptosis and ferroptosis and effective suppression of the TGF-β signaling pathway. Finally, DDP/IN-3@Gd-Fe NPs were found to remodel the immunosuppressive TME by increasing inflammatory mediators and promoting tumor infiltration of cytotoxic T cells and dendritic cells. In conclusion, DDP/IN-3@Gd-Fe NPs provide an MRI-traceable chemo-ferroptosis platform that may attenuate TGF-β-associated immunosuppression and improve checkpoint blockade responses in ovarian carcinoma. Download: Download high-res image (168KB) Download: Download full-size image
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Jingyu Wang,Xiaoli Guo,Yujiao Chen,Wei Zhang,Jing Ren,Ai Gao
Chronic benzene exposure causes hematotoxicity, yet the underlying molecular mechanisms remain incompletely understood. N6-methyladenosine (m6A) RNA modification has emerged as a critical regulator in various diseases, but its role in benzene-induced hematotoxicity is unclear. In this study, m6A mRNA microarray analysis revealed widespread alterations in m6A methylation following benzene exposure. Gene Ontology (GO) enrichment identified ubiquitin conjugating enzyme E2 G2 (UBE2G2) as a key m6A-methylated transcript associated with protein degradation pathways. Bioinformatics prediction and experimental validation (RIP-qPCR and MeRIP-qPCR) confirmed that the m6A reader YTHDF3 directly binds to UBE2G2 mRNA in an m6A-dependent manner. Benzene exposure downregulated YTHDF3 expression, leading to decreased UBE2G2 mRNA stability and expression. Overexpression of YTHDF3 reversed this suppression, confirming the regulatory relationship. Functionally, reduced UBE2G2 impaired ubiquitination of acyl-CoA synthetase long-chain family member 4 (ACSL4), resulting in its stabilization and upregulation, which promoted lipid peroxidation and ferroptosis. Notably, melatonin treatment ameliorated benzene-induced hematotoxicity by restoring the YTHDF3/UBE2G2/ACSL4 axis. In summary, this study identifies a novel epigenetic pathway—YTHDF3/m6A/UBE2G2/ACSL4—that mediates benzene-induced ferroptosis, and demonstrates the protective effect of melatonin through modulation of this axis.
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