INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Qiang Li,Yanbin Zheng,Jianyu Zhao,Xinyi Wei,Zongxin Shi,Haonan Fan,Chenxu Ge,Minxuan Xu,Jun Tan
Chronic kidney disease (CKD) presents a significant public health concern, with obesity being a prominent contributing factor to kidney disorders by inducing oxidative stress, lipotoxicity, and tubular cell injury. Natural anthocyanins extracted from red radishes ( Raphanus sativus L.) exert antioxidant and anti-apoptotic functions. This study aims to employ a novel natural pigment anthocyanin, referred to as radish red (RR) isolated from red radishes, to alleviate obesity-related metabolic disturbances and kidney impairment in a CKD mouse model induced by high-fat and high-fructose diets (HFFD). The in vitro study initially demonstrated that RR treatment significantly mitigated the palmitate acid (PA)-induced injury and cytotoxicity in human tubular epithelial HK2 cells. Subsequently, RR supplementation notably improved obesity and associated metabolic dysfunctions in mice caused by HFFD . Abnormal renal function indices including serum creatinine, blood urea nitrogen (BUN), uric acid (UA), urine protein, albuminuria and urine albumin-to-creatinine ratio (UACR) were detected in HFFD-fed mice, which were effectively alleviated by RR treatment. Histologically, renal tubular cell injury, lipid deposition, tubular dilatation, and renal fibrosis induced by HFFD were markedly improved after RR administration in mice. Furthermore, RR treatment significantly alleviated oxidative stress in HFFD-fed mice, as evidenced by the decreased renal reactive oxygen species (ROS) production, 4-HNE, and NOX4 expression levels. Anti-oxidants such as superoxide dismutase-1 (SOD1), NAD (P) H: quinone oxidoreductase (NQO1), heme oxygenase-1 (HO-1) and glutamate cysteine ligase (GCLC) were highly upregulated in kidney of HFFD-fed mice with RR consumption through improving NFE2-related factor 2 (Nrf2) signaling activation. Furthermore, ferroptosis was identified in the kidneys of HFFD-fed mice, evidenced by the elevated levels of malondialdehyde (MDA), iron content, and lipid peroxidation, along with the decreased expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). These occurrences were significantly mitigated following RR treatment. Mechanistically, we further discovered that the suppressive effects of RR in restricting oxidative stress, ferroptosis, lipid accumulation, and injury of tubular epithelial cells induced by PA were significantly counteracted by Nrf2 knockdown. Collectively, our results demonstrated that dietary supplementation with RR could potentially serve as an efficacious therapeutic modality for the management of obesity-related CKD progression by enhancing Nrf2 activation to impede oxidative stress and ferroptosis.
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BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Dan Wang,Ziran Yu,Ranqi Yao,Jingnan Zhang,Wenqi Cui,Jiaohua Dai,Jian Li,Heng Qian,Xiujuan Zhao
Perimenopausal depression is a subtype of depression and is prevalent among perimenopausal women, which has brought a heavy burden to family and society. The pathogenesis of perimenopausal depression is still unclear, which affects the prevention and treatment of perimenopausal depression to a certain extent. Quercetin is a flavonoid compound, and has estrogenic activity and pharmacological effects such as antioxidant, anti-inflammatory, and neuroprotective effects. This study investigated whether quercetin improved perimenopausal depression-like behaviors and potential mechanism. The results demonstrated that quercetin could alleviate the depression-like behaviors in perimenopausal depression rat model, inhibit astrocyte activation, improve ferroptosis-associated mitochondrial damage (such as mitochondrial pyknosis and mitochondrial cristae reduction) in hypothalamus, increase the expressions of histone 3 lysine 9 acetylation (acetyl-H3K9), ferroptosis-associated protein including glutathione peroxidase 4 (GPX4) and Xc- antiporter (SLC7A11), and reduce the expressions of endoplasmic reticulum stress-related proteins including inositol-requiring enzyme 1 (IRE1α), phosphorylated IRE1α (p-IRE1α), X-box binding protein 1 (XBP1) and glucose-regulated protein 78 (GRP78) in hypothalamus of perimenopausal depression rat model. Furtherly, in vitro study indicated that quercetin could restore histone acetylase (HAT)/histone deacetylase (HDAC) homeostasis through binding to estrogen receptors and increase the expression of acetyl-H3K9, inhibiting ferroptosis through IRE1α/XBP1 pathway in astrocytes of hypothalamus. Our findings demonstrated that acetyl-H3K9 is a crucial target in development of perimenopausal depression, and quercetin exhibited antidepressant effects through modulating acetyl-H3K9 mediated ferroptosis in perimenopausal depression. Quercetin might be the prevention and adjuvant treatment strategy of perimenopausal depression.
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ACS Nano
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2025
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IF 16
Jinzhao Liu,Meicen Wu,Chang Yang,Yang Zhou,Xinran Qi,Kang Chen,Xiaoping Zhang,Ni Fan,Changyou Zhan,Weiping Wang
Metastasis and immune escape play crucial roles in the progression of colon cancer. Current chemotherapy and immunotherapy treatments have limited effectiveness in reversing the immunologically cold microenvironment. Therefore, it is essential to investigate efficient strategies to enhance the antitumor immunity. In this study, ferroptosis suppressor protein 1 (FSP1) siRNA and photosensitizer Verteporfin were incorporated into the lipid nanoparticle (LNP) formulation for synergistic colon cancer immunotherapy. We first screened the photosensitive LNP formulations using different types of light-responsive small molecules. The selected photosensitive LNPs were further optimized by modulating surface properties to improve cellular uptake and endosomal escape levels in colon cancer cells. Upon light irradiation, the engineered photosensitive LNPs promoted synergistic ferroptosis by FSP1 gene silencing and oxidative stress, thereby causing immunogenic cell death to stimulate dendritic cell maturation and cytotoxic T lymphocyte response. In a bilateral tumor model, photosensitive LNPs exhibited potent antitumor efficacy and robust immunostimulatory effect upon light irradiation, enabling safe and efficient colon cancer treatment. This study demonstrates a synergistic potential between FSP1 gene silencing and photodynamic therapy, expanding the applications of photosensitive LNPs in clinical cancer treatment.
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ACS Omega
·
2025
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IF 4.3
Suyun Rao,Ke Xiao,Xuhui Chen,Xufang Sun
Diabetic retinopathy (DR) is a major cause of vision impairment, with diabetic retinal neurodegeneration (DRN) identified as an early pathological feature. Although dopamine (DA) has demonstrated protective effects in various neurodegenerative diseases, its role in DRN is inadequately understood. This study provides evidence that DA can alleviate DRN impairment and elucidates the underlying mechanisms. Diabetes was induced in C57BL/6 mice through a single large dose injection of streptozotocin, and the dopamine precursor l-DOPA was administered via intraperitoneal injection daily for 2 weeks to therapeutically supplement dopamine levels. The results indicated that l-DOPA treatment significantly restored retinal thickness, enhanced the amplitude of oscillatory potentials, and alleviated retinal glial cell activation compared to diabetic mice. In vitro, DA treatment of SH-SY5Y cells under high-glucose stress led to a significant increase in superoxide dismutase activity, with a reduction in malondialdehyde levels, lipid peroxide, and iron ion concentration. Additionally, the expression of GPX4, SLC7A11, ferritin, Nrf2, and HO-1 proteins was upregulated, while the expression of NCOA4 was downregulated. Importantly, the protective effects of DA were significantly attenuated by the Nrf2 inhibitor ML385, confirming the involvement of the Nrf2/HO-1 pathway in DA’s protective mechanism. These findings suggest that DA alleviates oxidative stress, reduces ferroptosis, and improves the retinal function in DRN through the activation of the Nrf2/HO-1 pathway, indicating that DA may represent a novel therapeutic strategy for treating DRN.
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COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2025
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IF 4.3
Tianyu Zhao,Yuping Zhang,Qianqian Song,Qingxuan Meng,Xinrui Meng,Xiaolong Wang,Jing Cong
Microrubber, a subset of microplastics, has raised global concerns due to its persistence and ecological risks in aquatic systems. This study systematically compared the toxicity of leachates (0, 0.5, 2.5, 5, 7.5, and 10 g/L) from tire wear particles (TWP) and latex particles (LAP) in zebrafish embryos for 5 days, integrating physiological endpoints, oxidative stress biomarkers, and transcriptomic profiling. LAP leachate exhibited significantly higher toxicity than TWP, causing increased mortality (100 % vs. 56.3 %), delayed hatching (0 % vs. 35.4 %), and severe malformations (e.g., tail and spine curvature). Chemical analyses identified elevated levels of heavy metals and biologically active organic compounds in LAP leachate, including higher zinc concentrations and benzothiazole derivatives, likely contributing to its greater toxicity. Oxidative stress markers revealed that LAP exposure induced a 1.46-fold increase in malondialdehyde (MDA) and suppressed glutathione S-transferase (GST) activity (31.6 % reduction), indicating impaired detoxification. Transcriptomics identified ferroptosis as a central putative toxicity pathway: LAP exposure was associated with dysregulated iron metabolism genes ( mt2 ↑, fthl31 ↑, slc40a1 ↓), and an exacerbation of lipid peroxidation, whereas TWP exposure was linked to adaptive responses via cyp1a and gstt1b upregulation. Functional rescue experiments using ferrostatin-1 further supported the involvement of ferroptosis, showing consistent but non-significant trends of physiological mitigation. These findings highlight distinct mechanistic pathways: LAP exposure correlated with pathways consistent with iron dyshomeostasis-driven ferroptosis, while TWP exposure appeared to induce phase I/II detoxification, providing molecular insights into microrubber toxicity. The study underscores the urgent need for source-specific risk assessments and regulatory measures to mitigate microrubber pollution in aquatic ecosystems.
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Drug Design Development and Therapy
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2025
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IF 5.1
Yijing Zhou,Chengli Lou,Xiuqin Xu,Bo Feng,Xiaoping Fan,Xiangjing Wang
Purpose Ursolic acid (UA) improves diabetic nephropathy (DN), but its regulatory mechanism requires further verification.Methods The bioactive component-target network of UA in DN was determined using a network pharmacology approach. DN mice (STZ-diabetic C57BL/6 mice, n = 8/group, 4 weeks) were treated with UA (25 mg/kg and 100 mg/kg) and the JAK agonist RO8191 (2 mg/kg). The DN cell model (high glucose-injured NRK-52E cells) was treated with UA (10 and 50 µM) and RO8191 (2 μM) for 24 h. The molecular mechanisms by which UA acts were further verified in vivo and in vitro.Results UA treatment ameliorated the general state of the DN mouse model, as characterized by the attenuation of weight loss and downregulation of fasting blood glucose (FBG) and fasting serum insulin (FINS) levels (all P < 0.05). Renal pathological changes and impaired renal function (increased levels of Scr, BUN, and UAER) were also improved by UA treatment (all P < 0.05). In vitro, UA increased the viability of DN cells in vitro (P < 0.001). Concurrently, UA remarkably downregulated the levels of ROS, SOD, and iron and up-regulated the levels of MDA, GPX4, and SLC7A11 (all P < 0.05) in vivo and in vitro. Mechanistically, activation of the JAK2-STAT3 pathway with the agonist RO8191 significantly reduced UA’s anti-ferroptosis and anti-oxidative effects of UA.Conclusion UA protected against DN by blocking JAK2/STAT3-mediated ferroptosis.
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Theranostics
·
2025
·Vol. 15
·期 17
·8757
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IF 13.3
Hui Yuan,Xiongwu Li,Muhua Yu,Youde Cao,Lingcheng Wu,Suyujie Shi,Yaying Yang,Kexiao Yu,Bing Liang
Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, characterized by the absence of targeted therapies and poor clinical outcomes. The development of novel, effective therapeutic strategies is urgently required to improve patient prognosis. Ferroptosis, a regulated form of cell death, has recently emerged as a promising therapeutic approach for TNBC. Objectives: This study aims to evaluate the efficacy of an injectable silk fibroin (SF)-based platform in treating TNBC and to explore the underlying mechanisms involved. Methods: We engineered an injectable SF platform consisting of magnetic, thermoresponsive silk fibroin-based hydrogels (IMSFs) coupled with temporally controlled TAT-Beclin1 delivery. Ferroptosis induction was quantified using the C11-BODIPY probe and transmission electron microscopy (TEM). To investigate the molecular mechanisms, RNA sequencing, Western blotting, and co-immunoprecipitation were performed. Additionally, enzyme-linked immunosorbent assay (ELISA) and flow cytometry were used to assess immune responses. Results: In the presence of an alternating magnetic field (AMF), IMSFs induce localized hyperthermia (42-45 °C) and catalyze Fenton reaction-driven reactive oxygen species (ROS) generation through Fe²⁺/Fe³⁺ release. The resulting ROS synergize with sorafenib release to inhibit the Xc⁻ system via the AMPK-Beclin1-SLC7A11 axis, leading to the local suppression of glutathione peroxidase 4 (GPX4) activity and the initiation of a ferroptosis cascade. Temporal delivery of TAT-Beclin1 prevents premature activation of autophagy, which could otherwise dampen ferroptosis. Instead, this approach leverages autophagy-ferroptosis synergy to amplify immunogenic cell death (ICD). This, in turn, activates CD8 + T cells, triggering interferon-gamma (IFN-γ)-mediated downregulation of SLC7A11 and establishing a self-amplifying cascade of “ferroptosis-autophagy-immunity” loop that induces oxidative stress and leads to enhanced anti-tumor effects. Conclusion: The injectable SF platform, incorporating sequential therapeutic modules, demonstrates potent anti-tumor efficacy and holds significant promise for clinical translation in the treatment of TNBC.
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JOURNAL OF FISH DISEASES
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2025
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IF 2.2
Bo Li,Penghui Yu,Lei Su,Jianguo Su,Yu Gao,Gailing Yuan
Aeromonas hydrophila- induced bacterial sepsis is a major threat to aquaculture, characterised by excessive inflammation, ferroptosis (an iron-dependent lipid peroxidation-driven cell death) and oxidative damage, which collectively lead to high mortality. Taurine (TAU) and glutathione (GSH) have been demonstrated to have potential therapeutic efficacy against ferroptosis-associated pathologies through redox modulation. However, their combined effects and underlying mechanisms in alleviating A. hydrophila infection remain unclear. In this study, we investigated the protective roles of TAU, GSH and their combination in vitro using yellow catfish ( Pelteobagrus fulvidraco ) macrophages and grass carp ( Ctenopharyngodon idella ) kidney (CIK) cells and in vivo using yellow catfish challenged with A. hydrophila . The results showed that TAU and GSH, either alone or in combination, alleviated oxidative stress by significantly reducing reactive oxygen species (ROS) accumulation and inhibited nuclear factor-κB (NF-κB) pathway activation. This led to downregulated expression of pro-inflammatory cytokines ( IL- 1β and TNF -α) and upregulated anti-inflammatory cytokines ( IL- 10 and TGF -β), accompanied by alleviated ferroptosis. In vivo, dietary supplementation with TAU (10 g/kg) or GSH (350 mg/kg) alone improved survival rates (51.7% and 38.3%, respectively), reduced tissue bacterial loads and protected intestinal and hepatic tissues by preserving mucosal barrier function. However, the TAU + GSH combination unexpectedly decreased survival (28.3%) due to excessive immunosuppression (overproduction of IL- 10 and TGF -β) and impaired mucosal barrier, which exacerbated pathogen colonisation. Together, our findings demonstrate that TAU and GSH alleviate A. hydrophila -induced oxidative stress by reducing mitochondrial ROS overproduction and disrupting the ROS/NF-κB signalling pathway, thereby attenuating inflammatory cytokine storms and ferroptosis. These results provide novel insights into the pathological mechanisms of bacterial sepsis in fish and develop sustainable strategies to improve disease resistance in aquaculture.
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Advanced Science
·
2025
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IF 14.1
Long-Bo Yu,Peng Wang,Qing-Hua Shen,Qi-Xin Guan,Zhi-Yuan Li,Ying-Ying Han,Xin-Yi Zhang,Qing-Yuan Hu,Cai-Ping Tan
Photosensitizers engineered for spatiotemporal modulation of cluster of differentiation 47 (CD47) in hypoxic tumor microenvironments (TMEs) disrupt immunosuppressive circuits. Herein, we develop two Ir(III) complexes ( Ir1 and Ir2 ) that function as photodynamic therapy (PDT) agents via Type-I/II mechanisms, overcoming hypoxic constraints. Under 630 nm irradiation, Ir1 -mediated PDT ROS-dependently downregulates CD47, enabling spatial control that circumvents hematotoxicity. Concurrently, Ir1 -mediated PDT triggers immunogenic cell death (ICD) via ferroptosis-necroptosis synergy and blocks the CD47-SIRPα immune checkpoint, while promoting M1-polarization of tumor-associated macrophages. In 4T1 murine breast cancer models, Ir1 -PDT achieves potent tumor suppression and transforms immunologically “cold” tumors into “hot” lesions through the synergistic interplay of ICD and CD47 pathway disruption. Collectively, this work establishes a photodynamic CD47-signaling platform for precise immune modulation, offering a clinically translatable alternative to conventional CD47-targeting therapies.
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Heart Lung and Circulation
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2025
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IF 2.2
Dan-Qing Duan,Ming-Rui Li,Li-Qun Lu,Bi-Feng Yao,Lin-Lu Huang,Xiu-Ju Luo,Jun Peng
Background & Aim Ferroptosis is an iron-dependent cell death and contributes to myocardial ischaemia/reperfusion (I/R) injury. Downregulation of glutathione peroxidase 4 (GPX4) is a key factor to accelerate ferroptosis, but the underlying mechanisms are not fully elucidated. Solute carrier family 7A member 11 (SLC7A11) plays a key role in maintaining the normal level of GPX4, and its transcription is suppressed by p53, whose level is controlled by spermatogenesis-associated protein 2 (SPATA2)/cylindromatosis (CYLD) pathway in a de-ubiquitination-dependent way. This study aims to explore whether SPATA2/CYLD pathway promotes myocardial ferroptosis in rat hearts after I/R through p53-dependent inhibition of SLC7A11. Methods The rat hearts were subjected to 1 h-ischaemia plus 3 h-reperfusion to establish a myocardial I/R injury model, and H9c2 cells were subjected to 8 h-hypoxia plus 12 h-re-oxygenation (H/R) to mimic myocardial I/R injury in vitro. Results Both the rat hearts and the cultured cardiomyocytes showed elevated levels of SPATA2 and CYLD, concomitant with the increased p53 levels and the enhanced interaction between SPATA2 and CYLD; these phenomena were reversed by knockdown of SPATA2. Mechanistically, knockdown of SPATA2 restored the ubiquitination of p53 and decreased p53 level in the H/R-treated cardiomyocytes, accompanied by increases in the levels of SLC7A11 and GPX4, and reduction of ferroptosis. Furthermore, suppression of SPATA2 by lurasidone, a predicted inhibitor of SPATA2, in the I/R-treated rat hearts also achieved similar results. Conclusion SPATA2/CYLD pathway-dependent de-ubiquitylation of p53 promotes ferroptosis in rat heart after I/R through a mechanism involving suppression of SLC7A11.
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Nature Communications
·
2025
·Vol. 16
·期 1
·1-22
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IF 15.7
Wang Wenkai,Cheng Zhuo,Yu Miao,Liu Ke,Duan Hongli,Zhang Yang,Huang Xinle,Li Menghuan,Li Changqing,Hu Yan,Luo Zhong,Liu Minghan
Discectomy-induced ferroptosis of nucleus pulposus cells (NPCs) contributes to postoperative lumbar disc herniation (LDH) recurrence and intervertebral disc degeneration (IDD). We discover that nucleus pulposus progenitor cells (NPPCs) could imprint ferroptosis resistance into NPCs through exosome-dependent intercellular transmission of miR-221-3p. Based on these findings, we first develop synthetically-tailored NPPC-derived exosomes with enhanced miR-221-3p expression and NPC uptake capacity, which are integrated into an injectable hydrogel based on extracellular matrix (ECM) analogues. The ECM-mimetic hydrogel (HACS) serves as a biomimetic filler for the post-operative care of herniated discs, which could be facilely injected into the discectomy-established nucleus pulposus (NP) cavity for localized treatment. HACS-mediated in-situ exosome release in the NP cavity enables marked ferroptosis inhibition in NPCs that not only prevents LDH recurrence but also reverses the IDD symptoms, leading to robust restoration of NP structure and functions. In summary, this study offers a promising approach for treating disc herniation.
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PARTICULATE SCIENCE AND TECHNOLOGY
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2025
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IF 1.5
Xingwang Sun,Haibin Wu
Ferroptosis, which relies on iron (Fe) ions for the production of reactive oxygen species (ROS), is an effective approach for treating liver cancer. Cells will activate several mechanisms, such as decreasing Fe absorption and sequestering surplus Fe in ferritin, to diminish intracellular Fe levels. This study presents a straightforward, one-pot approach for the fabrication of bovine serum albumin (BS)-stabilized MnFe2O4 (MnFe@BS NPs) intended for liver cancer treatment in ferroptosis therapy. Cabozantinib (CA) and paclitaxel (PA), which can promote ferritin breakdown and augment uptake by elevating transferrin receptor and binding protein IRP2 levels, were encapsulated in MnFe@BS NPs to improve the liver cancer cytotoxic properties. The fabricated MnFe@BS-CA/PA NPs substantially elevate cellular Fe concentration, hence augmenting ROS production within HepG2 cells. Thus, the bimetallic nanozyme demonstrated a synergistic effect of MnFe, CA, and PA, providing a foundation for improving ferroptosis therapy for liver cancer.
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