Frontiers in Oncology
·
2025
·
IF 3.3
Jing Cheng,Zhihan Liu,Haibo Liu,Chao Fang,Jun Li
Colorectal cancer (CRC) is one of the most prevalent malignant tumors worldwide, with its pathogenesis tightly linked to the regulation of cell death. Ferroptosis plays a pivotal role in the initiation, progression, and treatment of CRC. In our previous studies, we demonstrated that PPP2CA knockdown enhances the malignant phenotype of CRC cells while increasing their susceptibility to ferroptosis, albeit this latter effect frequently mitigates the malignant phenotype. The present study aims to further elucidate the regulatory mechanism underlying the association between PPP2CA and ferroptosis. Lentiviral-mediated PPP2CA knockdown was performed in CRC cell lines HCT116 and SW480 to establish stable PPP2CA-knockdown models, and PPP2CA gene expression in these models was verified. Colony formation assays and scratch wound healing assays were used to assess the proliferative and migratory capacities of CRC cells after PPP2CA knockdown. Additionally, CRC samples from The Cancer Genome Atlas (TCGA) database were analyzed via bioinformatics approaches to identify ferroptosis-related genes closely correlated with PPP2CA, with subsequent validation in model cells. The STRING database was employed to analyze the interaction networks between PPP2CA and target ferroptosis-related genes, predict potential signaling pathways via which PPP2CA regulates cellular ferroptosis, and validate these findings in model cells. Compared with the control group, HCT116 and SW480 cells in the PPP2CA-knockdown group exhibited significantly enhanced proliferative and migratory capacities. Bioinformatics analysis identified the top 10 most significant ferroptosis-related genes associated with PPP2CA. Validation in model cells showed that the expression levels of transferrin receptor (TFRC) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were significantly upregulated. STRING analysis and in-model-cell validation indicated that increased mTOR phosphorylation subsequent to PPP2CA knockdown could upregulate the protein expression levels of transferrin receptor (TfR, encoded by the TFRC gene) and ACSL4, and this effect could be reversed by the mTOR inhibitor rapamycin. Thus, PPP2CA knockdown enhances the malignant phenotype of CRC cells, while potentially upregulating the expression of ferroptosis-related genes TFRC and ACSL4 via the mTOR signaling pathway, thereby increasing ferroptosis sensitivity.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
癌症研究
·
信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Abdul Mueed,He Ma,Abdul Basit,Philippe Madjirebaye,Akhtar Ali,Shoaib Khan,Jing Li,Ze-yuan Deng
Flaxseed cyclolinopeptides (CLs) inhibit the lipid oxidation during in vitro digestion of high-fat meat. However, the effect of CLs on high-fat diet (HFD) induced lipid impairment metabolism remains unclear. Therefore, this study aimed to investigate the impact of CLs on HFD-induced lipid metabolism in the liver and pancreas of mice. The results demonstrated that the CLs administration significantly improved serum lipids (TG, TC, and LDL-C) in the HFD-induced model ( p < 0.05). Histological analysis using H&E and immunofluorescence staining revealed that CLs significantly restored pancreatic structure, and enhanced the secretion of insulin and glucagon. Furthermore, CLs intervention significantly improved antioxidant capacity in both the liver and pancrease by increasing the level of GSH-Px, T-GSH and GSH while decreasing GSSG and MDA levels in HFD-induced model. Lipidomic analysis further revealed that CLs treatment significantly reduced the levels of several lipid metabolites, including lysophosphatidylcholines (LPC), phosphatidylinositols (PI), lysophosphatidylethanolamines (LPE), phosphatidylethanolamines (PE), fatty acyls (FA), and diacylglycerols (DG), while increasing the levels of sphingomyelins (SM) and phosphatidylcholines (PC) compared to the model group. Pathway enrichment analysis indicated that CLs promoted the fatty acids metabolism and biosynthesis of unsaturated fatty acid, as supported by the upregulated expression of lipid metabolism gene/protien (CPT1, SLC7A11 and GPX4) and downregulated expression of lipid tranporter gene/protien (CD36, ACSL4, LPCAT3, and P35). Collectively, these findings suggest that CLs effectively enhance hepatic and pancreatic functiona and inhibit lipid accumulation in liver and pancreas through modulation of the CD36/p53/ACSL4 signalling pathway.
研究领域:
营养科学
·
生物化学
·
分子生物学
·
药理学
·
代谢性疾病
✓ 已验证
DOI
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-17
·
IF 14.7
Wang Huirui,You Xiaona,Wang Jingcheng,Chen Xinyi,Gao Yinghui,Wang Mengmeng,Zhang Wenru,Zhang Jiaozhen,Yu Yang,Han Bo,Qi Mei,Liu Xiaohui,Lou Hongxiang,Dong Ting
Hemolysis drives susceptibility to lung injury and predicts poor outcomes in diseases, such as malaria and sickle cell disease (SCD). However, the underlying pathological mechanism remains elusive. Here, we report that major facilitator superfamily domain containing 7 C (MFSD7C) protects the lung from hemolytic-induced damage by preventing ferroptosis. Mechanistically, MFSD7C deficiency in HuLEC-5A cells leads to mitochondrial dysfunction, lipid remodeling and dysregulation of ACSL4 and GPX4, thereby enhancing lipid peroxidation and promoting ferroptosis. Furthermore, systemic administration of MFSD7C mRNA-loaded nanoparticles effectively prevents lung injury in hemolytic mice, such as HbSS-Townes mice and PHZ-challenged 7 C −/− mice. These findings present the detailed link between hemolytic complications and ferroptosis, providing potential therapeutic targets for patients with hemolytic disorders.
研究领域:
分子生物学
·
细胞生物学
·
药理学
·
病理学
✓ 已验证
DOI
PubMed
高影响因子
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2025
·
IF 4
Hao Wu,Tong Xu,Naixi Yang,Shiwen Xu
Microplastics (MPs) and Emamectin Benzoate (EMB) were identified as hazardous environmental pollutants, frequently coexisting in aquatic ecosystems, posing potential risk in the immune system of human and animal. However, the hazards of concurrent exposed to MPs and EMB on the carp spleen, and the specific mechanisms remain unclear. Here, we employed MPs and EMB-exposed carp models, and cultured splenocytes in vitro, to demonstrate that PPARα signals suppression underlay MPs and EMB-induced carp spleen injury, based on transcriptomics and lipomics analysis. This suppression exacerbated the buildup of polyunsaturated fatty acid (PUFA), and promoted ACSL4 expression, resulting in increased lipid peroxidation. Further studies found that the accumulation of lipid peroxides predominantly occurred in the mitochondria, which evoked mitochondrial homeostasis imbalance and compromised mitochondrial function, thereby initiating ferroptosis. Additionally, enhancing PPARα signaling, inhibiting ACSL4, or scavenging mitochondrial ROS was favor of mitigating accumulation of lipid peroxides, reducing mitochondrial damage and inhibiting ferroptosis. Notably, MPs and EMB co-exposure caused more severe damage than single exposure. These findings uncovered a potential mechanism, involving PPARα signaling inhibition by MPs and EMB co-exposure, which evoked lipid remodeling and increased ACSL4, to drive ferroptosis and carp splenic injury. This study highlighted the potential hazards to the aquaculture environments where co-exposure of MPs and EMB and provided reference for environmental toxicology research and the sustainable development of the aquaculture industry.
研究领域:
环境毒理学
·
水产养殖学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Shouchun Xiao,Jingna Cui,Jiaxing Yang,Haonan Hou,Jianing Yao,Xiaoran Ma,Li Zheng,Fanrong Zhao,Xueke Liu,Donghui Liu,Zhiqiang Zhou,Peng Wang
Famoxadone is a chiral fungicide frequently found in the environment and agricultural products. However, the health risks of famoxadone enantiomers are not well understood. This study investigated the stereoselective cytotoxicity and metabolic behavior of famoxadone enantiomers in mammals. Results showed that R -famoxadone was 1.5 times more toxic to HepG2 cells than S -famoxadone. R -famoxadone induced more pronounced ferroptosis compared to S -famoxadone. It caused greater upregulation of genes related to iron transport and lipid peroxidation, and greater downregulation of genes related to peroxide clearance. Furthermore, R -famoxadone induced more severe lipid peroxidation and reactive oxygen species (ROS) accumulation through ACSL4 activation and GPX4 inhibition. Additionally, the bioavailability of R -famoxadone in mice was six times higher than that of S -famoxadone. Liver microsome assays, cytochrome P450 (CYP450) inhibition assays, human recombinant CYP450 assays, and molecular docking suggested that the lower binding affinities of CYP2C8, CYP2C19, and CYP2E1 for R -famoxadone caused its preferential accumulation. Overall, R -famoxadone poses a higher risk than S -famoxadone due to its greater cytotoxicity and persistence. This study provides the first evidence of ferroptosis-induced stereoselective toxicity, offering insights for the comprehensive health risk assessment of chiral famoxadone and valuable references for the application of high-efficiency, low-risk pesticide enantiomers.
研究领域:
毒理学
·
药理学
·
分子生物学
·
环境科学
✓ 已验证
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2022
·
IF 4.85
Yao Ding,Qinan Wu
Background Type 2 diabetes mellitus (T2DM) is a global health problem that seriously threatens human health. Vitamin D (VD) has antidiabetic effects. However, the protective mechanism of 1,25-dihydroxyvitamin D3 (1,25D) on T2DM is still unclear. Methods A rat model of T2DM was constructed using a high-fat diet combined with intraperitoneal injection of streptozotocin (STZ). Glucose tolerance was assessed by an oral glucose tolerance test (OGTT). Insulin secretion in blood and cell supernatant was determined by ELISA. Cell viability was analysed by CCK-8 assay. The level of ROS was detected by the DCFH-DA fluorescent probe method. The iron level in pancreatic tissues and cells was detected by an iron assay kit. Immunofluorescence staining was used to detect the expression of the pancreatic β cell marker CD49a . Furthermore, the protein expression levels of ferroptosis pathway-related proteins and vitamin D receptor (VDR) were detected by western blot . Downstream VDR targets were screened by proteomic sequencing. Results The DM group had increased glucose levels and decreased insulin secretion, while 1,25D treatment decreased glucose levels and increased insulin secretion. 1,25D also suppressed DM-induced ferroptosis in pancreatic tissues in vivo. In addition, 1,25D significantly enhanced the viability of pancreatic β cells and reduced the levels of ROS and iron. 1,25D significantly upregulated the expression of VDR and the ferroptosis-related pathway protein GPX4 and downregulated the expression of ACSL4. Furthermore, knockdown of VDR reversed the effects of 1,25D on cell viability, ROS and iron levels, and ferroptosis-related protein expression in pancreatic β cells. Proteomic sequencing revealed that FOXO1 was the downstream target gene of VDR. Knockdown of FOXO1 reduced pancreatic β cell death, decreased ROS, iron and ACSL4 levels, and increased GPX4 levels. Conclusion 1,25D/VDR inhibited pancreatic β cell ferroptosis in T2DM by downregulating the expression of FOXO1. This study provides a new theoretical basis for basic research on T2DM and is expected to establish a new idea for the treatment of T2DM.
研究领域:
内分泌学
·
分子生物学
·
糖尿病研究
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Anwei Zhang,Zhiwei Liu,Ling Zou,Lu Yang,Yonghui Wu,Xinxing Wang,Daigui Cao,Junli Liu,Xiaochao Yang,Shengli Zhang
Osteoporosis induced by the long-term administration of glucocorticoids is a common clinical problem. Current anti-osteoporosis therapies mainly focus on bone resorption inhibition or bone formation promotion unilaterally. However, the imbalance between bone formation and resorption often leads to suboptimal therapeutic outcomes. This study confirms the pathways through which dexamethasone (DEX), a typical glucocorticoid, triggers GIO, and explores both the therapeutic potential and underlying mechanisms of ceria nanoparticles (CNPs) in mitigating GIO. Our results demonstrate that DEX-induced bone homeostasis imbalance is the primary mechanism underlying GIO development in mice. Specifically, DEX inhibits pre-osteoblast proliferation and differentiation by inducing apoptosis and ferroptosis. Concurrently, DEX promotes osteoclast precursor proliferation and differentiation, significantly accelerating bone resorption. Administration of CNPs significantly mitigates DEX-induced disruption of bone homeostasis by ameliorating intracellular reactive oxygen species (ROS) accumulation via regulation of the Keap1/Nrf2 signaling pathway. Regarding osteogenesis, CNPs are capable of alleviating DEX-induced pre-osteoblast apoptosis and ferroptosis through the regulation of GPX4/ACSL4 signaling pathway. In terms of bone resorption, CNPs inhibit the RANKL-dependent osteoclast formation pathway. These findings validate the potential application of inorganic nanoparticles in GIO prevention.
研究领域:
纳米医学
·
骨骼生物学
·
药理学
·
分子生物学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2021
·
IF 11.799
Sufang Shui,Zenglu Zhao,Hao Wang,Marcus Conrad,Guoquan Liu
Ferroptosis is primarily triggered by a failure of the glutathione (GSH)-glutathione peroxidase 4 (GPX4) reductive system and associated overwhelming lipid peroxidation, in which enzymes regulating polyunsaturated fatty acid (PUFA) metabolism, and in particular acyl-CoA synthetase long chain family member 4 (ACSL4), are central. Here, we found that exogenous oxygen radicals generated by photodynamic therapy (PDT) can directly peroxidize PUFAs and initiate lipid autoxidation, coinciding with cellular GSH depletion. Different from canonical ferroptosis induced by RSL3 or erastin, PDT-initiated lipid peroxidation and ferroptotis-like cell death is independent of lipoxygenase (ALOXs) and ACSL4. Especially, this form of cell death modality can be triggered in malignant cells insensitive to or acquired resistance to canonical ferroptosis inducers. We also observed a distinct iron metabolism pathway in this PDT-triggered cell death modality, in which cytosolic labile iron is decreased probably due to its relocation to mitochondria. Inhibition of the mitochondrial Ca 2+ and Fe 2+ uniporter (MCU) effectively prevented PDT-triggered lipid peroxidation and subsequent cell death. Therefore, we tentatively term this distinct ferroptosis-like cell death as liperoptosis. Moreover, using the clinically approved photosensitizer Verteporfin, PDT inhibited tumor growth through inducing prevailing ferroptosis-like cell death in a mouse xenograft model. With its site-specific advantages, these findings highlight the value of using PDT to trigger lipid peroxidation and ferroptosis-like cell death in vivo , and will benefit exploring the exact molecular mechanism of immunological effects of PDT in cancer treatment.
研究领域:
肿瘤学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Kai Yuan,Yiqi Yang,Yixuan Lin,Feng Zhou,Kai Huang,Shengbing Yang,Weiqing Kong,Fupeng Li,Tianyou Kan,Yao Wang,Caiqi Cheng,Yakun Liang,Haishuang Chang,Jie Huang,Haiyong Ao,Zhifeng Yu,Hanjun Li,Yihao Liu,Tingting Tang
The specific mechanisms underlying bacteria-triggered cell death and osteogenic dysfunction in host bone marrow mesenchymal stem cells (BMSCs) remain unclear, posing a significant challenge to the repair of infected bone defects. This study identifies ferroptosis as the predominant cause of BMSCs death in the infected bone microenvironment. Mechanistically, the bacteria-induced activation of the innate immune response in BMSCs leads to upregulation and phosphorylation of interferon regulatory factor 7 (IRF7), thus facilitating IRF7-dependent ferroptosis of BMSCs through the transcriptional upregulation of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4). Moreover, it is found that intervening in ferroptosis can partially rescue cell injuries and osteogenic dysfunction. Based on these findings, a hydrogel composite 3D-printed scaffold is designed with reactive oxygen species (ROS)-responsive release of antibacterial quaternized chitosan and sustained delivery of the ferroptosis inhibitor Ferrostatin-1 (Fer-1), capable of eradicating pathogens and promoting bone regeneration in a rat model of infected bone defects. Together, this study suggests that ferroptosis of BMSCs is a promising therapeutic target for infected bone defect repair.
研究领域:
细胞生物学
·
干细胞研究
·
组织工程
·
再生医学
·
生物医学工程
·
传染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）