PATHOLOGY RESEARCH AND PRACTICE
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2025
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IF 3.2
Ting-Ting Yang,Xin-Xin Ma,Xuan Zhang,Zhen-Qing Han,Shuang Zhang,Qi Wang,Hong-Wei Dong,Jia-Ren Liu
β-Ionone (BI) has shown the potent inhibitory malignant progression of multiple tumors including gastric cancer in vitro and in vivo. However, the mechanism by which BI inhibits gastric cancer remains to be clarified, especially in ferroptosis, which is a new form of programmed cell death. The aim of this study was to investigate whether BI could induce ferroptosis in gastric cancer and the underlying mechanisms. The results manifested that BI obviously inhibited cell viability and increased the Fe 2 + level, total reactive oxygen species (ROS) and lipid ROS levels and the malondialdehyde (MDA) concentrations, but reduced the mitochondrial membrane potential (MMP) and the expression of SLC7A11 and GPX4 in MKN45 cells and AGS cells ( P < 0.05 or P < 0.01). Besides, BI also arrested cell cycle and decreased the expression of Cyclin D1 and CDK4 ( P < 0.05 or P < 0.01). Mechanistically, BI reduced the levels of β-catenin and pGSK-3β/GSK-3β in MKN45 cells and AGS cells ( P < 0.05 or P < 0.01). Nevertheless, pretreatment with lithium chloride (LiCl), an inhibitor of GSK-3β, reversed BI-induced ferroptosis and cell cycle arrested in MKN45 cells ( P < 0.05). In addition, BI effectively inhibited the growth of gastric cancer xenografts and downregulated the levels of GPX4, SLC7A11, PCNA, β-catenin and pGSK-3β/GSK-3β ( P < 0.05 or P < 0.01). Collectively, our study reveals that BI inhibits proliferation of gastric cancer cells by induction ferroptosis via the Wnt/β-catenin signaling pathway and provides a novel therapy for gastric cancer.
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Food & Function
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2025
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IF 5.4
Dapeng Chen,Jiayi Li,Xinyu Li,Kexin Zhang,Shujie Zeng,Shenjun Zhang,Longyun Li,Yongjian Xiong
Hispidulin, a dietary flavonoid occurring naturally in brown algae, has attracted considerable interest owing to its functions in modulating inflammatory responses and neutralizing reactive oxygen species. This study examined the consequences of hispidulin in a model of chemically induced acute colitis. RNA sequencing (RNA-seq), 16s rRNA-seq, and non-targeted metabolome were conducted to determine the mechanisms underlying hispidulin-induced effects on colitis. The findings revealed that hispidulin exhibited significant therapeutic benefits against colitis. In addition, treatment with hispidulin led to a decrease in pro-inflammatory cytokine levels as well as serum FITC-dextran concentrations. RNA-seq analysis demonstrated a notable increase in colonic ACAT2 expression in mice with colitis following hispidulin treatment. Furthermore, hispidulin administration resulted in the upregulation of GPX4, a reduction in ROS levels, and inhibition of epithelial ferroptosis in mice with colitis. Both genetic inhibition of ACAT2 in vitro and AAV-mediated knockdown of ACAT2 in vivo substantially negated the effects of hispidulin on GPX4/GSH levels, ROS levels, and lipid hydroperoxide accumulation in both NCM460 cells and epithelial cells derived from DSS exposed murine models. 16s rRNA-seq results showed that hispidulin increased abundance of Lactobacillus, NK4A136_group, Oscillibacter, Peptococcus, Adlercreutzia and decreased abundance of Turicimonas in colitic mice. Non-targeted metabolome results showed that hispidulin facilitated the metabolism of galactose and promoted unsaturated fatty acid biosynthesis in colitic mice. In summary, hispidulin reduced the advancement of acute colitis in mice by lessening ACAT2-mediated ferroptosis in epithelial cells, as well as altering composition of gut microbiota.
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Acta Biomaterialia
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2025
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IF 9.6
Xiaokang Zhu,Li Xie,Qing Liao,Jinming Tian,Jinlin Peng,Zhu Chen,Erqun Song,Yang Song
Ferrotherapy has risen as a promising therapeutic approach for triple-negative breast cancer (TNBC); however, its potency is frequently compromised due to tumor cells’ ability to evade ferroptosis via various resistance pathways and insufficient immunogenicity. To overcome these limitations, we have engineered a calcium phosphate-mineralized ferroptosis inducer nanoplatform, termed Lf-PEG-CaP@iFSP1-Brequinar-Erastin-Fe 3+ -TA (LP-CaP@iBEFT), designed to augment ferroptosis by simultaneously targeting three key pathways: glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and dihydroorotate dehydrogenase (DHODH). Once internalized and reached the acidic tumor microenvironment (TME), the nanoplatform discharges its therapeutic payloads, comprising inhibitors of FSP1 (iFSP), brequinar, erastin, and iron ions. The first three components were tailored to inhibit key pathways to ferroptosis, while the released iron ions initiate ferroptosis by catalyzing the generation of reactive oxygen species (ROS) via Fenton reactions. The calcium phosphate-mineralized ferroptosis inducer nanoplatform promotes the maturation of DC cells, enhances the infiltration of T cells and releases immunity-related factors, thereby altering the immunosuppressive microenvironment. In conjunction with anti-PD-L1 therapy, LP-CaP@iBEFT boosts T lymphocyte-mediated immune infiltration, thereby amplifying the anti-tumor response and offering a therapeutic approach for TNBC. Statement of significance We developed an acid-responsive nanoplatform that specifically targets tumor cells that overexpress lactoferrin receptors. This nanoplatform degrades within the acidic tumor environment to release the payload components iFSP1, brequinar, erastin, and Fe 3+ , which collectively inhibit three pathways of ferroptosis. This approach effectively dismantles the “triple defense” mechanism that tumor cells employ to resist ferroptosis. In addition, this nanoplatform synergizes with anti-PD-L1 immune checkpoint blockade, enhancing the T cell-mediated destruction of tumor cells.
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Clinical and Experimental Obstetrics & Gynecology
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2025
·Vol. 52
·期 11
·41496
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IF 0.6
Jiao Cai,Fengqi Wan,Jumei Yang,Yalan Wang,Jiao Wang
Background:Polycystic ovary syndrome (PCOS) is related to persistent low-grade inflammation and oxidative stress (OS). Resveratrol (RSV) exhibits potent anti-inflammatory and antioxidant effects, suggesting therapeutic potential for PCOS. However, its precise mechanisms of action, particularly concerning ferroptosis remain unclear. This study aimed to investigate whether RSV ameliorates PCOS by modulating inflammation, OS and ferroptosis features, thereby offering novel insights into its therapeutic role.Methods:PCOS was induced in mice through once-daily subcutaneous dosing of dehydroepiandrosterone (DHEA: 0.6 mg/kg), alongside a 21-day continuous high-fat diet regimen. Following successful model induction, the mice were assigned to the PCOS group or the RSV group. RSV was orally gavaged at doses of 20 and 40 mg/kg/day for 30 days. The body weight, ovarian weight and estrous cycle were monitored. Serum is used for the detection of hormones [follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T) and inflammatory markers [interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)]. Then the ovarian tissue samples were utilized for the assessment of OS indicators [malondialdehyde (MDA), glutathione (GSH)], glutathione peroxidase 4 (GPX4), and transcriptomic profiling.Results:RSV was shown to reduce body weight and ovarian weight. RSV also ameliorated symptoms of PCOS by decreasing chronic inflammation, OS and ferroptosis features in the ovaries. All the detected inflammatory factors in the PCOS group were significantly higher than those in the control group (IL-1β, p < 0.0001; IL-6, p < 0.001; TNF-α, p < 0.01) and were significantly decreased with the supplementation of RSV. Ovarian tissue MDA levels were markedly elevated in PCOS mice compared to controls (p < 0.0001), with RSV treatment significantly attenuating this increase. While GSH levels were significantly depleted in PCOS ovaries compared to controls (p < 0.0001), with RSV treatment effectively restoring concentrations. Western blot analysis revealed that GPX4 expression in ovaries was significantly diminished in the PCOS group compared with the control group (p < 0.01), but this reduction was effectively reversed by RSV treatment.Conclusions:RSV demonstrated therapeutic efficacy in PCOS mice by normalizing hormonal profiles and mitigating chronic inflammatory responses and oxidative damage. Furthermore, our investigation also revealed that RSV ameliorates PCOS pathology by modulating GPX4 pathways, which is consistent with ferroptosis features.
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TISSUE & CELL
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2025
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IF 2.5
Jie Liu,Yuan-Yuan Xu,Tian-Ye Gao
Background Diabetic kidney disease (DKD) is a severe microvascular complication, and ferroptosis is a major contributor to its pathogenesis. This study investigated the protective effects of Qingyu formula (QYF), a traditional Chinese medicine prescription, against ferroptosis in high glucose-induced renal injury. Methods In vitro, human renal tubular cells (human kidney 2 [HK-2]) under high glucose conditions were treated with QYF. In vivo, the induced diabetic mice received QYF interventions. Biochemical and molecular assays assessed cell viability, oxidative stress, ferroptosis markers (Fe²⁺, glutathione [GSH], malondialdehyde) and nuclear factor erythroid 2-related factor 2/solute carrier family 7 member 11/glutathione peroxidase 4 (Nrf2/SLC7A11/GPX4) pathway activity. Results Qingyu formula enhanced cell viability and reduced reactive oxygen species in high glucose-treated HK-2 cells. It mitigated ferroptosis by decreasing Fe²⁺ accumulation and increasing GSH levels both in vivo and in vitro. Mechanistically, QYF upregulated GPX4, Nrf2 and SLC7A11. In diabetic mice, it improved metabolic parameters and reduced proteinuria in a dose-dependent manner, with high doses showing efficacy similar to that of clinically used irbesartan. Conclusions Qingyu formula protects against high glucose-induced renal injury by suppressing ferroptosis via the activation of the Nrf2/SLC7A11/GPX4 pathway. These findings support QYF as a promising candidate for targeting ferroptosis in DKD. Future studies should identify its active constituents and evaluate its efficacy in clinical trials.
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Nutrients
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2025
·Vol. 17
·期 21
·3463
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IF 5
Yang Liu,Jingzhong Zheng,Xin Zheng,Dan Zhou,Hang Ma,Xue Zhou,Fahuan Ge
Background:Cili (Rosa roxburghiiTratt) is a unique fruit native to China’s Yunnan–Guizhou Plateau, rich in vitamin C, polyphenols, and triterpene, with broad health-promoting effects. Although cili’s hepatoprotective properties are reported, the bioactive components and underlying mechanisms remain poorly defined.Methods:We enriched proanthocyanidins from cili using column chromatography, identified their components via UPLC-Q-TOF-MS/MS, and validated their anti-liver fibrosis effects through in vitro and in vivo experiments.Results:Herein, we developed a novel proanthocyanidin-rich cili fruit extract (PACs-CFE) containing 84.2% total proanthocyanidins, comprising catechins, epicatechins, and diverse B-type dimers, trimers, tetramers, and gallate esters, as characterized by UPLC-Q-TOF-MS/MS. PACs-CFE inhibited LX-2 activation, suppressed collagen III and α-SMA expression, and induced ferroptosis via mitochondrial injury, reactive oxygen species accumulation, and GPX4/ferritin downregulation. In vivo, PACs-CFE ameliorated liver fibrosis, restored hepatic architecture, and improved serum alanine aminotransferase, aspartate aminotransferase, and bilirubin profiles. Moreover, PACs-CFE modulated the TGF-β1/Smad3 signaling pathway and beneficially reshaped the gut microbiota, enriching anti-inflammatory and hepatoprotective genera while reducing pathogenic taxa.Conclusions:Our findings show that PACs-CFE exerts multi-targeted anti-fibrotic effects through hepatic stellate cell inactivation, ferroptosis induction, TGF-β1/Smad3 suppression, and gut–liver axis modulation. This study provides useful insight into the hepatoprotective potential of cili fruit and supports its development as standardized functional ingredients for liver health.
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Oxidative Medicine and Cellular Longevity
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2022
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IF 7.31
Shiqi Gao,Liuzhi Zhou,Jianan Lu,Yuanjian Fang,Haijian Wu,Weilin Xu,Yuanbo Pan,Junjie Wang,Xiaoyu Wang,Jianmin Zhang,Anwen Shao
Background. Ferroptosis is a newly identified form of programmed cell death caused by iron-dependent lipid peroxidation. Our study was designed to determine the expression patterns and role of 15-lipoxygenase-1 (ALOX15) in subarachnoid hemorrhage (SAH) and to investigate whether cepharanthine (CEP) can inhibit ferroptosis by inhibiting ALOX15 in specific cell types. Methods. A mouse model of SAH was developed by the endovascular perforation method. bEend.3 endothelial cells and BV2 microglial cells as well as RSL3 and hemin were used to simulate SAH in vitro. Mice and cell lines were treated with CEP and a group of specific oxygenase inhibitors to explore the protection effect from ferroptosis. Lipid peroxidation staining with BODIPY 581/591 C11 and transmission electron microscopy were used to identify ferroptosis in vitro and in vivo. Results. In the present study, the accumulation of lipid peroxide, a defect in the glutathione peroxidase 4 (GPx4)/glutathione (GSH) antioxidant system, highly expressed ALOX15 in microglia and endothelium, and ferroptotic changes in microglial mitochondria confirmed the occurrence of ferroptosis after SAH in vivo. Further, CEP was shown to inhibit ferroptosis and improve neurological function by downregulating the expression of ALOX15. During in vitro experiments, we investigated the important role ALOX15 in RSL3-induced endothelial ferroptosis. In addition, we found that M2-type microglia are more sensitive to RSL3-induced ferroptosis than M1-type microglia and that hemin probably induced ferroptosis in M2-type microglia by increasing ALOX15 levels and decreasing GPx4 levels. The effect of CEP treatment was also demonstrated in vitro. Conclusions. In summary, to the best of our knowledge, this is the first study demonstrating that ferroptosis occurred in the microglia and endothelium after SAH, and this process was facilitated by increased ALOX15 levels. More importantly, treatment with CEP could inhibit ferroptosis through downregulating the expression of ALOX15.
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Ruijing Li,Weili Yang,Lijuan Zheng,Xingxue Yan,Cuihua Liu,Yaodong Zhang,Jitong Li
Prenatal alcohol exposure is a leading cause of developmental abnormalities and neurobehavioral deficits, collectively known as fetal alcohol spectrum disorder (FASD). The underlying molecular mechanisms, however, are not fully elucidated, hindering the development of effective therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key pathological process in various diseases. Gastrodin (GAS), the primary bioactive component of Gastrodia elata , has demonstrated potent antioxidant and neuroprotective properties. This study aimed to investigate the protective effects of GAS against alcohol-induced developmental and neurotoxic damage and to elucidate the underlying molecular mechanisms. Using a zebrafish larval model, we found that exposure to 200 mM alcohol from 2 to 24 hours post-fertilization (hpf) induced significant developmental toxicity, including a decreased hatching rate, body length and eye diameter, and increased morphological malformations in larvae. Alcohol-exposed larvae also exhibited severe neurobehavioral deficits, characterized by a reduction in movement distance and average velocity in dark conditions. Mechanistically, alcohol exposure triggered ferroptosis, evidenced by an increase in intracellular Fe 2+ , malondialdehyde (MDA), and reactive oxygen species (ROS) levels, alongside a decrease in the levels of glutathione (GSH) and reduced glutathione peroxidase 4 (GPX4) and the nuclear factor erythroid 2-related factor 2 (Nrf2) activities. Co-treatment with GAS (200 mg/L) significantly ameliorated these alcohol-induced developmental and neurobehavioral defects. GAS administration effectively suppressed the hallmarks of ferroptosis by restoring the ROS level and altering the expression of genes related to oxidative stress. In addition, GAS suppressed alcohol-induced cell apoptosis, downregulated caspase3b , bax , caspase8 , and upregulated bcl2 in mRNA levels. Molecular analysis revealed that GAS exerts its anti-ferroptotic effect by activating Nrf2/GPX4 signaling pathway, which was suppressed by alcohol. Our findings indicate that ferroptosis plays a key role in alcohol-induced developmental neurotoxicity, and GAS provides protection by activating the Nrf2/GPX4 axis. This suggests that GAS could be a potential therapeutic option for reducing the negative effects of prenatal alcohol exposure.
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Scientific Reports
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2022
·Vol. 12
·期 1
·1-11
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IF 4.996
Wan Yiting,Gu Cancan,Kong Jueying,Sui Jin,Zuo Ling,Song Yanhua,Chen Jing
Endometriosis (EMs) is one of the most frequent diseases of reproductive-age women and is characterized by the growth of endometrial tissues beyond the uterus. The enhanced proliferative and migratory potential of endometrial stromal cells (ESCs) plays an important role in the progression of EMs. Mounting studies have demonstrated that long noncoding RNAs (lncRNAs) exert an important role in regulating the development and progression of EMs. Given the aberrant expression of lncRNA ADAMTS9-AS1 in ectopic endometrium (ecEM), we investigated the biological effect of ADAMTS9-AS1 on ESC proliferation and migration and explored the underlying mechanism. The current data showed that ADAMTS9-AS1 expression was significantly upregulated in ecEM compared with eutopic endometrium (euEM) in patients with EMs and in a murine model of EMs. Functionally, ADAMTS9-AS1 knockdown in ectopic ESCs (EESCs) decreased cell viability and migration, whereas ADAMTS9-AS1 overexpression in normal ESCs (NESCs) enhanced cell viability and migration. More importantly, the effect of ADAMTS9-AS1 inhibition on decreasing ESC viability was significantly blocked by ferrostatin-1 (Fer-1, a ferroptosis inhibitor), and ADAMTS9-AS1 overexpression repressed erastin (a ferroptosis activator)-induced cell death. Furthermore, the regulatory role of ADAMTS9-AS1 in ferroptosis was defined and evidenced by increased reactive oxygen species (ROS) levels and malonyl dialdehyde (MDA) content and decreased expression of glutathione peroxidase 4 (GPX4) after ADAMTS9-AS1 inhibition. Mechanistically, ADAMTS9-AS1 functioned as a competing endogenous RNA (ceRNA) by sponging miR-6516-5p to derepress the expression of GPX4, the critical repressor of ferroptosis. Taken together, these results demonstrate that upregulated ADAMTS9-AS1 accelerates ESC proliferation and migration by regulating miR-6516-5p/GPX4-dependent ferroptosis and may be a potential target for the treatment of EMs.
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Advanced Healthcare Materials
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2025
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IF 9.6
Chen-Song Huang,Chunlei Dai,Qi Liu,Si-Yun Chen,Ya-Hao Guo,Jie-Qin Wang,An-Da Zheng,Xi-Tai Huang,Jun Wu,Xiao-Yu Yin
Ferroptosis has emerged as a critical mechanism in overcoming drug resistance in various tumors; however, its role in gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC) has not been thoroughly explored. Additionally, the effectiveness of ferroptosis in many cancer therapies has been limited. In our study, we found that GPX4 is upregulated in gemcitabine-resistant (GR) PDAC patient tissues and cell lines. Notably, inhibiting GPX4 can reverse gemcitabine resistance in PDAC through the induction of ferroptosis, highlighting it as a potential therapeutic target. To address this, we developed a novel nanomedicine, GSH-depleted and ferroptosis-induced (FiN), designed to encapsulate and deliver the GPX4 inhibitor RSL3, resulting in a dual ferroptosis-induced nanomedicine (DFiN). In a PDAC patient-derived xenograft (PDX) mouse model exhibiting gemcitabine resistance, DFiN demonstrated significant accumulation in GR PDAC tumors, leading to a reduction in intracellular GSH levels and inhibition of GPX4. This dual action promoted lipid peroxidation and synergistically induced ferroptosis, effectively reversing gemcitabine resistance. Both in vitro and in vivo experiments confirmed that DFiN is effective in overcoming gemcitabine resistance in GR PDAC cells and PDX tumors, with minimal toxicity observed. This study presents a promising strategy for addressing drug resistance in cancer therapy.
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Huimei Zhao,Haiyan Zhang,Jianyu Shi,Yanru Liu,Jingao Yu,Yuangui Yang,Jingyu Weng,Zhongxing Song,Rui Zhou,Hong Min,Jian Yao,Mei Wang,Zhen Zhang
Ethnopharmacological relevance Asthma is a chronic inflammatory airway disease. Current treatments have limited efficacy and often cause severe side effects. Wuwei Shaji Powder (WSP), a traditional Mongolian remedy, is used for treating chronic pulmonary diseases, but its efficacy against asthma and underlying mechanisms are still unclear. Aim of the study To investigate the therapeutic effect of WSP on asthma and elucidate its molecular mechanisms. Materials and methods An ovalbumin (OVA)-induced allergic asthma model was established in rats. Ferroptosis or apoptosis was induced in BEAS-2B cells using Erastin or CdCl 2 . Various techniques including histopathological staining, ELISA, Western blot, flow cytometry, and transmission electron microscopy were employed to assess WSP's effects and mechanisms. Results WSP alleviated OVA-induced allergic asthma in rats without the immunosuppressive side effects observed with dexamethasone. WSP suppressed ferroptosis in bronchial epithelial cells both in vivo and in vitro. It reduced thiol- and sulfonic-based oxidative stress through Keap1 S-sulfhydration, disrupted the Keap1-Nrf2 interaction, and promoted Nrf2 nuclear translocation. Notably, we discovered that CdCl 2 can induce ferroptosis in BEAS-2B cells, and WSP prevented both ferroptosis and apoptosis in these cells. Conclusion WSP alleviates OVA-induced allergic asthma by protecting bronchial epithelial cells from ferroptosis via S-sulfhydration of Keap1, providing new insights for its clinical application.
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ARCHIVES OF TOXICOLOGY
·
2024
·
IF 4.8
Wang Yanwei,Qiu Jingru,Yan Hua,Zhang Nan,Gao Shixuan,Xu Ning,Wang Cuiyan,Lou Haiyan
Doxorubicin (DOX) is one of the most frequently used chemotherapeutic drugs belonging to the class of anthracyclines. However, the cardiotoxic effects of anthracyclines limit their clinical use. Recent studies have suggested that ferroptosis is the main underlying pathogenetic mechanism of DOX-induced cardiomyopathy (DIC). BTB-and-CNC homology 1 (Bach1) acts as a key role in the regulation of ferroptosis. However, the mechanistic role of Bach1 in DIC remains unclear. Therefore, this study aimed to investigate the underlying mechanistic role of Bach1 in DOX-induced cardiotoxicity using the DIC mice in vivo (DOX at cumulative dose of 20 mg/kg) and the DOX-treated H9c2 cardiomyocytes in vitro (1 μM). Our results show a marked upregulation in the expression of Bach1 in the cardiac tissues of the DOX-treated mice and the DOX-treated cardiomyocytes. However, Bach1 −/− mice exhibited reduced lipid peroxidation and less severe cardiomyopathy after DOX treatment. Bach1 knockdown protected against DOX-induced ferroptosis in both in vivo and in vitro models. Ferrostatin-1 (Fer-1), a potent inhibitor of ferroptosis, significantly alleviated DOX-induced cardiac damage. However, the cardioprotective effects of Bach1 knockdown were reversed by pre-treatment with Zinc Protoporphyrin (ZnPP), a selective inhibitor of heme oxygenase-1(HO-1). Taken together, these findings demonstrated that Bach1 promoted oxidative stress and ferroptosis through suppressing the expression of HO-1. Therefore, Bach1 may present as a promising new therapeutic target for the prevention and early intervention of DOX-induced cardiotoxicity.
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