Frontiers in Immunology
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2026
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IF 7
Xiaokun Shen,Haitao Cao,Fujie Li,Wenya Wang,Xingshu Qi,Yarui Zhou,Bo Li,Qingjie Fan,Tao Yang,Shinan Li
Liver fibrosis is a major global health challenge, and it is an independent risk factor for the development of hepatocellular carcinoma (HCC). Several methods have been explored to improve liver fibrosis progression, but effective preventive and therapeutic strategies remain limited. Natural killer (NK) cells can limit the activation of hepatic stellate cells (HSCs), but they have exhibited impaired antifibrotic properties in liver fibrosis, and the underlying mechanisms are not well understood. In this study, we found that CD36 was markedly upregulated in NK cells from mice with liver fibrosis. The CD36 expression was negatively correlated with activation markers of NK cells. The CD36- NK cells exhibited elevated cytotoxic cytokine production and enhanced antifibrotic activity against HSCs. The adoptive transfer of CD36- NK cells alleviated liver fibrosis progression. Mechanistically, CD36 induced reactive oxygen species (ROS) and lipid peroxidation. These consequently triggered ferroptosis in NK cells. The blockage of CD36 or inhibition of ferroptosis in NK cells effectively restored their antifibrotic properties against HSCs. In summary, our findings demonstrated that the antifibrotic properties of NK cells were regulated by CD36. These results provide evidence that targeting CD36 could restore NK cell function for liver fibrosis immunotherapy.
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Advances in Pharmacological and Pharmaceutical Sciences
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2026
·Vol. 2026
·期 1
·7893262
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IF 2.9
Jiaxiang Liao,Zitian Wang,Zhou Huang,Jincheng Li,Jie Yang,Chunyun Fang,Dongling Huang,Fan Wang,Xueling Lu,Yiling Zhai,Wei Wang
Myocardial infarction (MI) involves a pathological process in which its association with ferroptosis is notably pronounced, and targeted regulation of ferroptosis presents a promising approach for treating MI. This work delineates the molecular basis by which the natural sesquiterpene germacrone protects against cardiomyocyte ferroptosis following isoproterenol (ISO)-induced MI. We established a murine model of ISO-induced MI, paired with an injured H9c2 cardiomyocyte model in vitro. Mice in the experimental group received daily oral germacrone (25, 50, and 100 mg/kg) for 7 consecutive days. We profiled myocardial injury markers and key nuclear factor erythroid 2–related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) axis proteins. The mechanism of action was confirmed by utilizing ML385, the Nrf2-specific inhibitor. Germacrone significantly reduced ISO-induced myocardial injury in mice, improving cardiac function and decreasing myocardial histopathological damage. Germacrone universally attenuated the elevation of myocardial injury and inflammatory markers in all experimental models. It also decreased the apoptosis rate of H9c2 cells. Germacrone inhibited myocardial ferroptosis and upregulated the abundance of pivotal regulatory proteins, including Nrf2, GPX4, and heme oxygenase-1 (HO-1), along with solute carrier family 7 member 11 (SLC7A11). ML385, an Nrf2 antagonist, can block germacrone’s protective effect against ISO-induced myocardial ferroptosis and reverse its upregulation of these pathway proteins. These findings provide a new potential target and experimental foundation for MI treatment.
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Genes & Diseases
·
2026
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IF 14.6
Xinhang Li,Yi Xie,Wenyan Ren,Qing Liu,Qiming Pang,Wenting Liu,Xin Li,Bin He,Dongmei He,Xinyue Wan,Jia Liu,Jie Cai,Baicheng He,Wei Huang,Fang He
Renal osteodystrophy is a debilitating complication of chronic kidney disease characterized by deteriorated bone microarchitecture and impaired bone formation, leading to increased fracture risk. Despite the pressing need for anabolic therapies, the cellular mechanisms by which uremic stress compromises osteoprogenitor function remain poorly defined. Here, metabolomic profiling of renal osteodystrophy patient cohorts revealed a profound depletion of circulating betaine. We show that betaine supplementation not only rescued the osteogenic differentiation of bone marrow-derived mesenchymal stem cells challenged with the uremic toxin indoxyl sulfate but also ameliorated skeletal deterioration in a rat model of chronic kidney disease. Mechanistically, we demonstrated that indoxyl sulfate triggered ferroptosis in bone marrow-derived mesenchymal stem cells—characterized by iron-dependent lipid peroxidation and aberrant HMOX1 up-regulation—thereby arresting osteogenesis. Betaine mitigates this ferroptotic stress through a novel post-transcriptional mechanism. Specifically, betaine down-regulated the RNA-binding protein hnRNP A1, preventing the recruitment of the CNOT1 deadenylase complex. This inhibition stabilized Abcg1 mRNA, leading to restored ABCG1 expression. Functional perturbation studies confirmed that the ABCG1–HMOX1 axis was indispensable for the anti-ferroptotic and osteoprotective effects of betaine. Collectively, our findings delineate a Betaine–hnRNP A1/CNOT1–ABCG1–HMOX1 signaling cascade that links metabolic deficiency to ferroptosis-driven osteogenic failure, positioning betaine as a promising anabolic therapeutic strategy for renal osteodystrophy.
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Materials Today Bio
·
2026
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IF 11
Yanxuan Xiao,Pengcheng Sun,Wenjie Xu,Xinyan Hao,Tiantian Tang,Xinying Liu,Hai Huang,Zhaojian Gong,Junyong Wu
Radiation-induced oral mucositis (RIOM) is the most common complication in patients receiving radiotherapy for head and neck, to which ferroptosis is an important contributor. Transferrin receptor (TFRC) -mediated endocytosis is a critical source of iron. Accordingly, we proposed that inhibiting ferroptosis by disrupting TFRC mediated-iron uptake. In this study, we developed endosome-targeting self-assembling nanoparticles (CB NPs) integrated into a detachable microneedle patch (CBT@MNs) for precise and synergistic RIOM therapy. This system integrated the clinically conventional drugs chloroquine and baicalin and loaded into MN patch for mucosal drug delivery. In the tongue mucosa, the MN tips released CB NPs. Upon entering endosomes through the endocytosis pathway, CB NPs disrupted endosomal acidification through the proton sponge effect, which may block TFRC recycling, achieving long-term inhibition of ferroptosis and inflammation efficacy. In rat models of RIOM, CBT@MNs dramatically attenuated mucosal ulceration and accelerated healing via anti-inflammation, angiogenesis, and collagen deposition. Transcriptomic analysis further revealed that CBT@MNs suppressed ferroptosis and inflammatory signaling. This radioprotective strategy for inhibiting ferroptosis and regulating redox homeostasis provided a novel approach for designing tissue engineering materials.
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MOLECULES
·
2026
·Vol. 31
·期 15
·2559
·
IF 5.1
Yiyao Gong,Jie Zhang,Tingting Wang,Xiang Li,Hao Wang,Li Ren
Chronic exposure to lead (Pb) represents a persistent environmental hazard that can impair hippocampal integrity and cognitive function, while effective protective strategies remain limited. Ginsenoside Rg1 is an important bioactive constituent derived fromPanax ginsengand has been reported to possess antioxidant and neuroprotective activities; however, its involvement in Pb-triggered ferroptosis-associated neuronal damage remains unclear. In the present study, a male C57BL/6J mouse model of subchronic lead acetate exposure and a lead-exposed HT22 cell model were established. Behavioral and histopathological changes were assessed, followed by analysis of inflammatory responses, oxidative stress, ferroptosis-related alterations, and Nrf2-associated signaling. Rg1 improved cognitive performance and attenuated hippocampal neuronal loss, neuroinflammatory activation, oxidative injury, and ferroptosis-related alterations, including ferrous ion accumulation and mitochondrial damage. Consistently, Rg1 restored SLC7A11/xCT and GPX4 expression and enhanced Nrf2-associated antioxidant signaling, whereas the Nrf2 inhibitor ML385 weakened the Rg1-induced increases in nuclear Nrf2, NQO1, and GPX4. Collectively, these findings indicate that Rg1 alleviates lead-induced neurotoxicity and support the involvement of Nrf2 signaling in the regulation of oxidative stress and ferroptosis-related injury. These findings provide experimental evidence supporting further preclinical investigation of Rg1 and its Nrf2-associated neuroprotective mechanisms in Pb-induced neuronal injury.
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高影响因子
Frontiers in Bioscience-Landmark
·
2026
·Vol. 31
·期 7
·
IF 4.1
Zhenxin Huo,Ding Li,Yuxuan Kuang,Baoshan Xu
Background: Intervertebral disc degeneration (IDD) is a major pathological contributor to low back pain, and its progression is closely associated with oxidative stress and cell death. Ferroptosis is a form of programmed cell death characterized by iron-dependent lipid peroxidation, which has recently been confirmed to participate in IDD progression. Microsomal glutathione S-transferase 1 (MGST1) plays an important role in glutathione metabolism and cellular antioxidant defense, but its function in IDD remains unclear. This study aimed to investigate the expression profile of MGST1 in IDD and to elucidate its molecular mechanism in delaying degeneration by regulating ferroptosis. Methods: Differentially expressed ferroptosis-related genes associated with intervertebral disc degeneration were screened through bioinformatics analysis. MGST1 expression changes were validated using a needle puncture-induced rat IDD model and a degenerated nucleus pulposus (NP) cell model. MGST1 knockdown and overexpression strategies were employed to evaluate its effects on the extracellular matrix metabolism, apoptosis, and senescence of nucleus pulposus cells. Further examinations of ferroptosis-related indicators were conducted, including levels of lipid peroxidation, reactive oxygen species generation, intracellular Fe2+ content, and changes in mitochondrial membrane potential. For in vivo experiments, the therapeutic effect of MGST1 overexpression was assessed by intradiscal injection of an MGST1-overexpressing lentivirus into the rat intervertebral disc degeneration model. Results: Bioinformatics analysis indicated that MGST1 is a key candidate gene in IDD. MGST1 expression was consistently upregulated with increasing degeneration severity in rat disc tissues and degenerated NP cells. Knockdown of MGST1 significantly promoted extracellular matrix degradation and increased apoptosis and senescence levels in NP cells, while MGST1 overexpression markedly improved these changes. Mechanistic studies revealed that MGST1 deficiency significantly enhanced ferroptosis characteristics in NP cells, including accumulation of lipid peroxides and ROS, increased Fe2+ content, and decreased mitochondrial membrane potential. In vivo experiments demonstrated that MGST1 overexpression significantly alleviated the degree of IDD in rats. Conclusion: MGST1 exhibits compensatory upregulation during the progression of intervertebral disc degeneration and delays its progression by inhibiting ferroptosis in nucleus pulposus cells. This study reveals a novel mechanism by which MGST1 regulates ferroptosis in IDD and provides a potential molecular target for the prevention and treatment of IDD.
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高影响因子
ACS Applied Nano Materials
·
2025
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IF 5.5
Jing Yu,Zhengtao Xu,Yiling Ruan,Jiarui Qi,Xiaolian Sun,Shenglei Che
Ferroptosis is an immunogenic form of cell death characterized by iron-dependent lipid peroxidation. The balance between Fe2+ and Fe3+ is crucial in inducing ferroptosis, where Fe2+ primarily initiates the Fenton reaction to generate reactive oxygen species (ROS), resulting in lipid peroxidation and subsequent cell damage. However, the instability of Fe2+, due to its susceptibility to oxidation into Fe3+, poses challenges for effectively triggering ferroptosis. In this study, we report a synthetic method for creating Fe2+-rich nanoworms regulated by oleyl amine, which effectively stabilizes Fe2+. These nanoworms exhibited exceptional efficacy in producing ROS through high Fe2+ proportion and glutathione (GSH) consumption by Fe3+, thereby initiating lipid peroxidation (LPO) and subsequent induction of ferroptosis and immunogenic cell death. The conjugation with tumor-penetrating peptide (iRGD) endowed the accumulation at tumor sites. After coupling with αPD-L1, these nanoworms significantly enhanced their tumor inhibition rate through the combination of ferroptosis and immunotherapy, reducing the tumor volume to 22.52%. This work provides a promising material for combined tumor therapy by inducing ferroptosis and downstream immunotherapy.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Huan Du,Guiqiang Qi,Minghui Zhao,Junyu Xie,Shouping Dai,Yusong Zhang,Chunhai Gao,Kang Chen,Ran Yan,Geng Yang
Mild photothermal therapy (mPTT) is often hindered by the upregulation of heat shock proteins (HSPs). To address this limitation, we designed a trienzyme-mimicking nanoreactor (MPGH) by functionalizing MnCO-loaded polydopamine (PDA) nanospheres with glucose oxidase (GOx)-doped hyaluronic acid. MPGH integrates the catalytic activities of GOx, peroxidase (POD), and glutathione peroxidase (GPX). Specifically, GOx consumes glucose to induce starvation therapy while simultaneously generating H 2 O 2 . The produced H 2 O 2 promotes MnCO decomposition, releasing CO for gas therapy and Mn 2+ to trigger mitochondrial dysfunction and reactive oxygen species (ROS) generation, thereby exhibiting POD-like activity. Meanwhile, the GPX-like activity of PDA depletes intracellular glutathione (GSH), downregulating glutathione peroxidase 4 (GPX4) to enhance ferroptosis. Importantly, both CO-mediated gas therapy and GOx-mediated starvation therapy disrupt cellular energy metabolism, reducing adenosine triphosphate (ATP) levels and suppressing HSP expression, which markedly enhances the efficacy of mPTT. This synergistic strategy of disrupting energy homeostasis demonstrated potent therapeutic outcomes against breast cancer.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Zhiyuan Niu,Shengbo Wu,He Ding,Xuexia Shan,Yuting Shen,Yuanbo Peng,Junjie Song,Shaoyue Li,Weichen Xu,Ying Wang,Mingliang Pei,Xiaodong Hou
Currently, while intravenous chemotherapy effectively targets tumor lesions, it also causes unavoidable systemic toxicity due to drug metabolism in the bloodstream and the toxicity to normal cells. To address this problem, an injectable and biodegradable fibrin-based gel was employed as a pharmacy scaffold, cladding FDA-approved DOX-loaded and hyaluronic acid (HA)-modified nanoparticles (DOX&FeP-HA@gel), aiming to achieve local tumor therapy through the combination of ferroptosis-DOX mediated self-enhancement therapy. The DOX&FeP-HA exhibited remarkable CD44 bio-targeting, medium stability, TME-triggered degradation, and continued release of drugs, achieving approximately 80 % cumulative release within 48 h. During this process, the released DOX induced apoptosis and generated abundant H 2 O 2 by mitochondrial activity. Simultaneously, intracellular H 2 O 2 reacted with Fe 2+ to produce highly toxic OH. Moreover, DOX&FeP-HA not only consumed GSH but also reduced GPX4 expression in tumor cells, thereby amplifying ferroptosis. To anchor nanoparticles in tumor tissue, an injection that utilizes fibrin-based gel was introduced. In live experiments, 4T1 tumor-bearing mice received optimal therapeutic outcomes with DOX&FeP-HA@gel treatment, achieving a 100 % survival rate over 30 days according to Kaplan-Meier survival analysis. Overall, a strategy of in situ injection gel carrying multifunctional nanoparticles was proposed, offering a promising new approach to tumor treatment with substantial potential for clinical applications.
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ACS Biomaterials Science & Engineering
·
2025
·
IF 5.5
Juan Huang,Mingjing Yang,Xingyu Zhou,Jigang Luo,Xiaoxia Yan,Guanghui Lin,Shijie Li,Shihui Liu,Zhuoyue Song,Chunzhi Tang,Nenggui Xu,Tao Liu,Jian Liang
Drug repurposing has received increasing attention in the field of oncology drug development as an alternative strategy to de novo drug synthesis. Disulfiram (DSF) has a long history of clinical application in alcohol withdrawal, and recent studies have revealed that its metabolite diethyldithiocarbamate (DDTC) can be coordinated with copper ions in vivo to form Cu-DDTC complexes with anticancer activity. However, the insufficient in vivo stability of DSF remains a challenge. In this study, the nanomedicine Cu-BTC@DDTC with DDTC-Cu(I) chemical valence and polycrystalline structure was prepared by incorporation of DDTC into the nanosized metal–organic framework (MOF) Cu-BTC. The in vitro cellular evaluation results showed that Cu-BTC@DDTC exhibited high inhibition of tumor cell growth, migration, and invasion. Animal experiments on the xenograft tumor model further demonstrated the excellent antitumor activity and biosafety of Cu-BTC@DDTC, and the antitumor activity was found to be closely related to the regulation of the SLC7A11/GPX4 signaling pathway to induce ferroptosis. This study provides a feasible option for antitumor drug development based on a drug repurposing strategy.
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FREE RADICAL RESEARCH
·
2025
·
IF 2.9
Doudou Lu,Ling Yuan,Zhaozhao Wang,Duojie Xu,Fandi Meng,Shumin Jia,Yahong Li,Weiqiang Li,Yi Nan
The prognosis of gastric cancer (GC) remains poor due to metastases and resistance to chemotherapy. Ferroptosis is a novel cell death regulation mode characterized by iron dependence and lipid peroxidation. Dioscin, a compound extracted from the Paris polyphylla rhizomes roots, has been shown to have an inhibitory effect on cancers. However, whether it induces ferroptosis to participate in anti-cancer metastasis remains unclear. The ability of gastric cancer cells to invade and migrate was evaluated by wound healing and transwell assays. Malondialdehyde (MDA), glutathione (GSH) assay kit, and dichlorofluorescin diacetate (DCFH-DA) fluorescent probes were used to detect ferroptosis in gastric cancer cells. The expression levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot methods. The rescue assay was performed by adding Ferrostatin-1 (Fer-1) co-treatment to verify that Dioscin inhibited gastric cancer metastasis by participating in ferroptosis. Dioscin inhibited gastric cancer cells’ wound healing, migration, and invasion process. In addition, Dioscin increased the level of reactive oxygen species (ROS) and MDA while decreasing GSH level, and induced ferroptosis of gastric cancer cells. Fer-1, an inhibitor of ferroptosis, could reverse the effect of Dioscin. In terms of mechanism, Dioscin induced ferroptosis through SLC7A11/GPX4 axis and was involved in the regulation of inhibiting metastasis of gastric cancer. These results suggested that Dioscin was involved in anti-cancer metastasis by inducing ferroptosis.
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高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Yi-lang Zhong,Zhi-qiang Liang,Can Hu,Chen-qin Xu,Miao-Miao Wang,Chao Ma,Cheng-lin Jia,Ye-min Cao,Yong-bing Cao,Ji Li,Jian-da Zhou,Jian Chen
Background Impaired healing of diabetic foot ulcers (DFU) is a major clinical challenge. This condition is driven by unresolved inflammation and cellular dysfunction. However, the specific role of macrophage ferroptosis in this process remains poorly defined. Purpose This study aimed to investigate the contribution of macrophage ferroptosis to DFU pathogenesis. We also evaluated the therapeutic effect and underlying mechanism of the Ruan Jian Qing Mai formula (RJQM). Our investigation focused on the NINJ1–ferroptosis–inflammation axis and its role in intercellular communication. Methods We combined single-cell RNA sequencing of human wound tissues with a streptozotocin-induced diabetic mouse model. The chemical composition of RJQM was characterized by HPLC-MS. For in vitro experiments, we used macrophages stimulated with high glucose and LPS to model diabetic conditions. Key markers for ferroptosis, inflammation, and signaling pathways were assessed using Western blot, qPCR, and flow cytometry. Finally, endothelial cell behavior was evaluated through migration and tube formation assays. Results Our analysis revealed that macrophages exhibited the highest ferroptosis activity in diabetic wounds. In diabetic mice, RJQM treatment accelerated wound healing in a ferroptosis-dependent manner. We identified 87 compounds in RJQM. These compounds effectively suppressed ferroptosis by enhancing GPX4/xCT expression while reducing lipid peroxidation and iron overload. Mechanistically, RJQM inhibited a positive feedback loop involving NINJ1 and ferroptosis, and also suppressed downstream STAT3 activation. Furthermore, conditioned media from RJQM-treated macrophages promoted endothelial migration and tube formation. This pro-angiogenic effect was reversed by NINJ1 overexpression, confirming its critical role. Conclusion RJQM promotes diabetic wound repair by targeting the NINJ1–STAT3–ferroptosis pathway in macrophages. This action reduces inflammation and restores the cells' pro-angiogenic functions. Our findings support RJQM as a promising therapeutic strategy for DFU.
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