PHYTOMEDICINE
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2024
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IF 6.7
Shanshan Guo,Lang Zhou,Xueqi Liu,Li Gao,Yuanyuan Li,Yonggui Wu
Background In acute kidney injury (AKI), ferroptosis is the main mechanism of cell death in the renal tubular epithelium. Baicalein, a traditional Chinese medicine monomer, plays a protective role in various kidney diseases; however, the effect of baicalein on ferroptosis in AKI still needs further exploration. Purpose In this study, we explored the role of baicalein and its specific mechanism in mediating ferroptosis in cisplatin-induced AKI. Methods We used a cisplatin-induced AKI model to study the effects of baicalein on renal tissue and tubular epithelial cell injury. The effects of baicalein on tubular epithelial cell ferroptosis were detected in cisplatin-induced AKI and further verified by folic acid-induced AKI. The Swiss Target Prediction online database was used to predict the possible mechanism by which baicalein regulates ferroptosis, and the specific target proteins were further verified. Molecular docking and SPR were used to further determine the binding potential of baicalein to the target protein. Finally, RNA interference (RNAi) technology and enzymatic inhibition were used to determine whether baicalein regulates ferroptosis through target proteins. Results Baicalein alleviated cisplatin- and folic acid-induced renal dysfunction and pathological damage and improved cisplatin-induced HK2 cell injury. Mechanistically, baicalein reduced the expression of 12-lipoxygenase (ALOX12), which inhibits phospholipid peroxidation and ferroptosis in AKI. Molecular docking and SPR demonstrated direct binding between baicalein and ALOX12. Finally, we found that silencing ALOX12 had a regulatory effect similar to that of baicalein. Comparable results were also obtained with the ALOX12 inhibitor ML355. Conclusion This was the first study to confirm that baicalein regulates ferroptosis both in vitro and in vivo in cisplatin-induced AKI and to verify the regulatory effect of baicalein in folic acid-induced AKI. Our results reveal the critical role of ALOX12 in kidney damage and ferroptosis caused by cisplatin and emphasize the regulatory effect of baicalein on renal tubular epithelial cell ferroptosis mediated by ALOX12. Baicalein is an effective drug for treating AKI, and ALOX12 is a potential drug target.
研究领域:
药理学
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肾病学
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细胞生物学
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分子生物学
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药物发现
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PubMed
高影响因子
Translational Cancer Research
·
2026
·Vol. 15
·期 7
·555
·
IF 2.1
Junjie Wu,Congxing Liu,Yaya Sun,Guangqing Jiang,Yupeng Zhao,Yihong Zhang,Yiping Yin,Xin Shi
Background Colon cancer (CC) is a heterogeneous disease with increasing morbidity and mortality. Ferroptosis, a recently identified form of regulated cell death (RCD) characterized by the massive accumulation of iron-dependent lipid peroxidation (LPO), has been proven to be closely associated with various biological behaviors of CC. Moreover, accumulating evidence reveals that ALOX12 is essential for p53-mediated ferroptosis through distinct pathways. Therefore, our study aims to explore the specific mechanisms by which ALOX12 regulates tumorigenesis in CC through ferroptosis pathway. Methods We explored the characteristics of ALOX12 expression and its correlation with prognosis in CC patients and cell lines, followed by a series of functional assays in vitro and in vivo to investigate the mechanisms underlying the functions of ALOX12 in p53-driven ferroptosis. Results We discovered that ALOX12 was downregulated in CC tissues and cell lines, which was correlated with poor prognosis. Furthermore, overexpression of ALOX12 suppressed cell proliferation and tumorigenesis by upregulating reactive oxygen species (ROS)-induced stress. We continuously found that increased ALOX12 levels enhanced the sensitivity of CC cells to a distinct ferroptosis, which required both p53 activation and additional ROS, and differed from that induced by erastin. Conclusions Our study demonstrates the oncosuppressive behavior of ALOX12 in CC. Mechanistically, we discover that p53 can indirectly activate ALOX12 function by suppressing its transcriptional target SLC7A11, resulting in an ALOX12-dependent ferroptotic pathway. Targeting ALOX12 may provide a novel biomarker or new therapeutic strategies for improving the prognosis of CC.
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高影响因子
TOXICOLOGY
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2026
·
IF 5.2
Yu Wang,Xu Han,Zizheng Wang,Yushan Song,Yiqiang Zhang,Mingwei Xing,Hongjing Zhao
Arsenic (As) is a widespread environmental toxicant that poses severe threats to animal and human health by disrupting multiple cellular processes. In this study, embryonic zebrafish fibroblast cells (ZF4) were used as an in vitro model to investigate the role of Alox12-mediated lipoxygenation in arsenite-induced ferroptosis. Transcriptomic analysis revealed that arsenite exposure (20 μM, 24–48 h) globally induced oxidative stress, apoptosis, cell cycle arrest, and autophagic cell death in a time-dependent manner. Notably, ferroptosis was absent at the early stage but became prominent upon prolonged exposure, coinciding with increased Alox12 expression and 12-HETE production. Overexpression of Alox12 under arsenite stress significantly elevated lipid peroxidation, ROS accumulation, and cell death, whereas siRNA-mediated knockdown of Alox12 partially rescued these phenotypes and restored GPx4 activity. These findings demonstrate that Alox12 mediates the transition from ferroptosis suppression to activation during arsenite toxicity, presenting a checkpoint-like phenotypic phenomenon. This work provides mechanistic insight into arsenism and a potential molecular target for ferroptosis-based therapeutic intervention.
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高影响因子
INFLAMMATION
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2026
·Vol. 49
·期 1
·92
·
IF 5.4
Shiying Lin,Xin Liu,Jian Jiang,Wenqiang Ge,Qingxiao Tao,Suwen Liu,Ouyang Zhanmu,Yang Yang,Man Li,Hongxiang Chen
The endogenous cannabinoid system, comprising endocannabinoids, cannabinoid receptors, and enzymes responsible for synthesis and degradation of endocannabinoids, is integral to the regulation of skin inflammation. However, the precise contributions of cannabinoid-metabolizing enzymes including fatty acid amide hydrolase and monoacylglycerol lipase (MAGL) remain poorly defined in psoriatic pathogenesis. In this study, we demonstrated the significant MAGL upregulation in psoriatic lesions and established that pharmacological inhibition of MAGL markedly reduced psoriasiform inflammation and pruritus in imiquimod-challenged C57BL/6 mice. Mechanically, inhibition of MAGL decreased the expression of 12-lipoxygenase (ALOX12), subsequently reducing the synthesis of 12-hydroxyeicosatetraenoic acid (12-HETE), which is the principal metabolite of ALOX12. Importantly, these effects were reversed by cannabinoid receptor 2 (CB2R) antagonism or knockout, establishing a signaling axis in which MAGL inhibition activates CB2R to suppress ALOX12. Collectively, our findings identified MAGL as a potentially targetable nexus in psoriasiform inflammation and itch.
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高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
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IF 6.6
HuaFeng Zeng,YuXi Li,HongTing Zhao,Lin Chen,Lin Xu,ShaoYing Wang,YuFan Zhang,HaoChen Wang,ShuYun Huang,Yunqiang Xu,Chunnian You,Lei Sun,FengZhen Cui,Huanwen Tang
As a Class I human carcinogen ubiquitous in both industrial and household environments, benzene can cause hematopoietic damage even at low concentrations. However, its precise hematological toxicological molecular mechanism remains incompletely understood. Here, we demonstrate that hydroquinone (HQ), a benzene metabolite, induces ferroptosis and endoplasmic reticulum stress (ERs) in TK6 cells. Mechanistically, through a combination of RNA-Seq and database analyses, we identified ATF3 as a central molecular switch linking ERs to ferroptosis following HQ treatment, with its activation mediated by the PERK pathway. Using oxidative lipidomics, we further identified ALOX12 as a key lipid peroxidase involved in promoting ferroptosis. Moreover, chromatin immunoprecipitation sequencing (ChIP-Seq) and dual-luciferase reporter assays revealed that ATF3 directly binds to the ALOX12 promoter, triggering its transcriptional activation, which in turn accelerates lipid peroxidation and ultimately leads to ferroptosis. In a mouse model of benzene-induced hematotoxicity, knockdown of ATF3 effectively inhibits bone marrow ferroptosis and markedly ameliorates hematopoietic impairment. Importantly, our cohort study revealed that the higher of ATF3, ALOX12, MDA, and lower GSH/GSSG was significantly associated with hematotoxicity in workers exposed to benzene. Collectively, these findings suggest the ATF3-ALOX12 signal axis may represent promising biomarkers for monitoring early hematopoietic damage resulting from low-dose benzene exposure in environmentally exposed populations.
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高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2023
·
IF 7.5
Yijing Yang,Ying Wang,Ying Deng,Jing Lu,Li Xiao,Jie Li,Yasha Zhou,Fujiao Nie,Xiangdong Chen,Jun Peng,Hanyu Tan,Yuhui Qin,Qinghua Peng
Aim of the study To assess the impact of Fructus Lycii and Salvia miltiorrhiza Bunge extract (FSE) on retinitis pigmentosa (RP) and to explore the mechanisms by which FSE can prevent oxidative stress-induced photoreceptor ferroptosis in RP. Methods Hydrogen peroxide(H 2 O 2 ) was used to induce oxidative stress in 661 W cells, which were then examined using flow cytometry and enzyme linked immunosorbent assay (ELISA). Changes in mitochondria were observed by using an electron microscope to characterize the ferroptosis of the cells. The protective effect of FSE on the retina function and structure of rd10 mice was evaluated using histopathological examination, fundus photographs, and electroretinography (ERG). Protein expression levels of Tumor Protein p53 (P53), Solute Carrier Family 7 Member 11 (SLC7A11), Glutathione peroxidase 4 (GPX4), Arachidonate-12-Lipoxygenase (ALOX12), and Dipeptidyl peptidase 4 (DPP4) were evaluated by Western blot assays in Vivo and in Vitro. Results H 2 O 2 -induced 661 W cells increased oxidative stress products and P53 and ALOX12, decreasing the expression of SLC7A11, GPX4, and DPP4. GPX4 activator does not reduce reactive oxygen species (ROS) generation and has little effect on ferroptosis. Fer-1 and FSE attenuate ROS generation and inhibit ferroptosis of photoreceptors in RP via inhibited P53 expression and increased SLC7A11 and GPX4 expression. Conclusion FSE may be available in clinical therapeutics to alleviating RP and the mechanism by which inhibits ferroptosis of photoreceptors following oxidative stress via the P53/ SLC7A11 pathway.
研究领域:
眼科学
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药理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
Antioxidants
·
2021
·Vol. 10
·期 6
·976
·
IF 6.313
Chongshan Dai,Hui Li,Yang Wang,Shusheng Tang,Tony Velkov,Jianzhong Shen
This study investigates the protective effect of baicalein on carbon tetrachloride (CCl4)-induced acute liver injury and the underlying molecular mechanisms. Mice were orally administrated baicalein at 25 and 100 mg/kg/day for 7 consecutive days or ferrostatin-1 (Fer-1) at 10 mg/kg was i.p. injected in mice at 2 and 24 h prior to CCl4injection or the vehicle. Our results showed that baicalein or Fer-1 supplementation significantly attenuated CCl4exposure-induced elevations of serum alanine aminotransferase and aspartate aminotransferase, and malondialdehyde levels in the liver tissues and unregulated glutathione levels. Baicalein treatment inhibited the nuclear factor kappa-B (NF-κB) pathway, activated the erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway in liver tissues, and markedly improved CCl4-induced apoptosis, inflammation and ferroptosis in liver tissues exposed with CCl4. In vitro, baicalein treatment improved CCl4-induced decreases of cell viabilities and knockdown ofNrf2and arachidonate 12-lipoxygenase (ALOX12) genes partly abolished the protective effect of baicalein on CCl4-induced cytotoxicity in HepG2 cells. In conclusion, our results reveal that baicalein supplementation ameliorates CCl4-induced acute liver injury in mice by upregulating the antioxidant defense pathways and downregulating oxidative stress, apoptosis, inflammation and ferroptosis, which involved the activation of Nrf2 pathway and the inhibition of ALOX12 and NF-κB pathways.Keywords:baicalein;oxidative stress;ferroptosis;acute liver injury;ALOX12 pathway;Nrf2 pathway
研究领域:
药理学
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肝病学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
·
2024
·
IF 3.1
Qiao Liu,Xiaoyuan Wu,Cuicui Liu,Ni Wang,Fengxia Yin,Huan Wu,Shijian Cao,Wenchen Zhao,Hongfei Wu,An Zhou
Wilson disease (WD) is an inherited disorder characterized by abnormal copper metabolism with complex pathological features. Currently, this mechanism of copper overload-induced hepatic injury remains unclear. In this study, male toxic milk (TX) mice were selected as experimental subjects. Copper levels and biochemical indices were measured by atomic absorption spectroscopy (AAS) and kits. Liver tissue ultrastructure was observed by hematoxylin-eosin (H&E), sirius red staining and transmission electron microscopy. Plasma and liver metabolic profiles of TX mice were characterized by untargeted metabolomics. In addition, the expression of enzymes related to arachidonic acid metabolism in liver tissue was detected by Western blotting. The results showed the excessive copper content, concomitant oxidative stress, and hepatic tissue structural damage in TX mice. Seventy-eight metabolites were significantly different in WD, mainly involved in the metabolism of arachidonic acid, glycerophospholipids, sphingolipids, niacin and nicotinamide, and phenylalanine. Furthermore, the arachidonic acid metabolic pathway is an important pathway involved in WD metabolism. The level of arachidonic acid in the liver of TX mice was significantly lower ( p < 0.01) compared to the control group. The expression of cytoplasmic phospholipase A2 (cPLA2) and arachidonic acid 12-lipoxygenase (ALOX12), related to the arachidonic acid metabolic pathway, was significantly different in the liver of TX mice ( p < 0.01). Modulation of the arachidonic acid metabolic pathway could be a potential therapeutic strategy to alleviate WD symptoms.
研究领域:
医学
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代谢组学
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生物化学
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病理学
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PubMed
高影响因子
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