BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Dandan Wu,Zongchao Zuo,Xinning Sun,Xin Li,Fangzhou Yin,Wu Yin
Long-chain fatty acyl-Coa ligase 4 (ACSL4) is an important enzyme that converts fatty acids to fatty acyl-Coa esters, there is increasing evidence for its role in carcinogenesis. However, the precise role of ACLS4 in hepatocellular carcinoma (HCC) is not clearly understood. In the present study, we provide evidence that ACSL4 expression was specifically elevated in HCC and is associated with poor clinical outcomes. ACSL4 significantly promotes the growth and metastasis of HCC both in vitro and in vivo . RNA sequencing and functional experiments showed that the effect of ACSL4 on HCC development was heavily dependent on PAK2. ACSL4 expression is well correlated with PAK2 in HCC, and ACSL4 even transcriptionally increased PAK2 gene expression mediated by Sp1. In addition, emodin, a naturally occurring anthraquinone derivative, inhibited HCC cell growth and tumor progression by targeting ACSL4. In summary, ACSL4 plays a novel oncogene in HCC development by regulating PAK2 transcription. Targeting ACSL4 could be useful in drug development and therapy for HCC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
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IF 4.7
You Zhou,You Wu,Rui Zhu
Background Septic acute kidney injury (S-AKI) is a major cause of acute kidney injury (AKI), but no effective therapies exist to prevent or treat it. Although KLF6 is linked to various pathophysiological processes, its exact role in S-AKI is not yet fully understood. Methods The role of KLF was investigated using both the mouse CLP model and in vitro systems. To identify the transcriptional targets regulated by KLF6, ChIP-qPCR and luciferase reporter assays were carried out. Biochemical and cellular techniques were employed to assess cellular injury and lipid peroxidation levels. The extent of ferroptosis was evaluated through transmission electron microscopy (TEM). Results KLF6 levels were significantly increased in a renal IRI model. Knockdown of KLF6 using AAV9 reduced kidney injury in both in vitro and in vivo models, while KLF6 overexpression aggravated injury. Overexpression of KLF6 promoted ferroptosis, whereas its knockdown reduced lipid peroxidation and ferroptosis. KLF6 regulates NCOA4 expression by binding to its promoter, controlling ferroptosis. Knockdown of NCOA4 in vitro alleviated ferroptosis and cellular damage caused by KLF6 overexpression. Pharmacological inhibition of KLF6 reduced kidney injury and ferroptosis in S-AKI mice. Conclusion Our study uncovered a previously unrecognized role for KLF6 in S-AKI. By facilitating NCOA4 transcription, KLF6 intensified ferroptosis, which, in turn, aggravated septic AKI.
研究领域:
肾脏病学
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分子生物学
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病理生理学
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细胞生物学
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转录调控
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DOI
PubMed
高影响因子
APOPTOSIS
·
2024
·Vol. 29
·期 9
·1679-1695
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IF 6.1
Fan Aoyu,Li Yunpeng,Zhang Yunyan,Meng Wei,Pan Wei,Chen Meixi,Ma Zhongliang,Chen Wei
Prostate cancer (PCa) is one of the most common cancers affecting the health of men worldwide. Castration-resistant prostate cancer (CRPC), the advanced and refractory phase of prostate cancer, has multiple mechanisms of resistance to androgen deprivation therapy (ADT) such as AR mutations, aberrant androgen synthase, and abnormal expression of AR-related genes. Based on the research of the AR pathway, new drugs for the treatment of CRPC have been developed in clinical practice, such as Abiraterone and enzalutamide. However, many areas in this pathway are still worth exploring. In this study, single-cell sequencing analysis was utilized to scrutinize significant genes in the androgen receptor (AR) pathway related to CRPC. Our analysis of single-cell sequencing combined with bulk-cell sequencing revealed a substantial downregulation of AR-regulated AFF3 in CRPC. Overexpression of AFF3 restricted the proliferation and migration of prostate cancer cells whilst also increasing their sensitivity towards enzalutamide, while knockdown of AFF3 had the opposite effect. To elucidate the mechanism of tumor inhibition by AFF3, we applied GSVA and GSEA to investigate the metabolic pathways related to AFF3 and revealed that AFF3 had an impact on fatty acids metabolism and ferroptosis through the regulation of ACSL4 protein expression. Based on correlation analysis and flow cytometry, we can speculate that AFF3 can impact the sensitivity of the CRPC cell lines to the ferroptosis inducer (RSL3) by regulating ACSL4. Therefore, our findings may provide new insights into the mechanisms of drug resistance in CRPC, and AFF3 may serve as a novel prognostic biomarker in prostate cancer.
研究领域:
肿瘤学
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分子生物学
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基因组学
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DOI
高影响因子
CELL
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2024
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IF 45.5
Yuqi Wang,Mangze Hu,Jian Cao,Fengxiang Wang,Jingrong Regina Han,Tianshu William Wu,Luxiao Li,Jinshi Yu,Yujing Fan,Guanglei Xie,Heyuan Lian,Yueying Cao,Nathchar Naowarojna,Xi Wang,Yilong Zou
Metastatic dissemination to distant organs demands that cancer cells possess high morphological and metabolic adaptability. However, contributions of the cellular lipidome to metastasis remain elusive. Here, we uncover a correlation between metastasis potential and ferroptosis susceptibility in multiple cancers. Metastases-derived cancer cells exhibited higher ferroptosis sensitivity and polyunsaturated fatty acyl (PUFA)-lipid contents than primary-tumor-derived cells from ovarian cancer patients. Metabolism-focused CRISPR screens in a mouse model for ovarian cancer distant metastasis established via two rounds of in vivo selection revealed the PUFA-lipid biosynthesis enzyme acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) as a pro-hematogenous metastasis factor. ACSL4 promotes metastatic extravasation by enhancing membrane fluidity and cellular invasiveness. While promoting metastasis, the high PUFA-lipid state creates dependencies on abhydrolase-domain-containing 6, acylglycerol lipase (ABHD6), enoyl-CoA delta isomerase 1 (ECI1), and enoyl-CoA hydratase 1 (ECH1)—rate-limiting enzymes preparing unsaturated fatty acids (UFAs) for β-oxidation. ACSL4/ECH1 co-inhibition achieved potent suppression of metastasis. Our work establishes the dual functions of PUFA-lipids in tumor progression and metastasis that may be exploitable for therapeutic development.
研究领域:
癌症生物学
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代谢生物学
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脂质代谢
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分子肿瘤学
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DOI
PubMed
高影响因子
MOLECULAR THERAPY
·
2023
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IF 12.4
Li Gao,Junsheng Zhang,Tingting Yang,Ling Jiang,Xueqi Liu,Sheng Wang,Xian Wang,Yuebo Huang,Huaying Wang,Mengya Zhang,Tingting Gong,Lijuan Ma,Chao Li,Chaoyong He,Xiao-ming Meng,Yonggui Wu
Hypertension is a primary modifiable risk factor for cardiovascular diseases, which often induces renal end-organ damage and complicates chronic kidney disease (CKD). In the present study, histological analysis of human kidney samples revealed that hypertension induced mtDNA leakage and promoted the expression of stimulator of interferon genes (STING) in renal epithelial cells. We used angiotensin II (AngII)- and 2K1C-treated mouse kidneys to elucidate the underlying mechanisms. Abnormal renal mtDNA packing caused by AngII promoted STING-dependent production of inflammatory cytokines, macrophage infiltration, and a fibrogenic response. STING knockout significantly decreased nuclear factor-κB activation and immune cell infiltration, attenuating tubule atrophy and extracellular matrix accumulation in vivo and in vitro . These effects delayed CKD progression. Immunoprecipitation assays and liquid chromatography-tandem mass spectrometry showed that STING and ACSL4 were directly combined at the D53 and K412 amino acids of ACSL4. Furthermore, STING induced renal inflammatory response and fibrosis through ACSL4-dependent ferroptosis. Last, inhibition of ACSL4 using small interfering RNA, rosiglitazone, or Fer-1 downregulated AngII-induced mtDNA-STING-dependent renal inflammation. These results suggest that targeting the STING/ACSL4 axis might represent a potential strategy for treating hypertension-associated CKD.
研究领域:
肾病学
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免疫学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2024
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IF 3.3
Li Tao,Yu-Feng Xue,Fei-Fei Sun,Xue He,Hong-Qian Wang,Cheng-Cheng Tong,Cheng Zhang,De-Xiang Xu,Xi Chen
Ferroptosis has been shown to be involved in carbon tetrachloride (CCl 4 )-induced acute liver injury (ALI). The mitochondrion-targeted antioxidant MitoQ can eliminate the production of mitochondrial reactive oxygen species (mtROS). This study investigated the role of MitoQ in CCl 4 -induced hepatocytic ferroptosis and ALI. MDA and 4HNE were elevated in CCl 4 -induced mice. In vitro, CCl 4 exposure elevated the levels of oxidized lipids in HepG2 cells. Alterations in the mitochondrial ultrastructure of hepatocytes were observed in the livers of CCl 4 -evoked mice. Ferrostatin-1 (Fer-1) attenuated CCl 4 -induced hepatic lipid peroxidation, mitochondrial ultrastructure alterations and ALI. Mechanistically, acyl-CoA synthetase long-chain family member 4 (ACSL4) was upregulated in CCl 4 -exposed human hepatocytes and mouse livers. The ACSL4 inhibitor rosiglitazone alleviated CCl 4 -induced hepatic lipid peroxidation and ALI. ACSL4 knockdown inhibited oxidized lipids in CCl 4 -exposed human hepatocytes. Moreover, CCl 4 exposure decreased the mitochondrial membrane potential and OXPHOS subunit levels and increased the mtROS level in HepG2 cells. Correspondingly, MitoQ pretreatment inhibited the upregulation of ACSL4 in CCl 4 -evoked mouse livers and HepG2 cells. MitoQ attenuated lipid peroxidation in vivo and in vitro after CCl 4 exposure. Finally, MitoQ pretreatment alleviated CCl 4 -induced hepatocytic ferroptosis and ALI. These findings suggest that MitoQ protects against hepatocyte ferroptosis in CCl 4 -induced ALI via the mtROS-ACSL4 pathway.
研究领域:
医学
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生物化学
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DOI
PubMed
高影响因子
Science Advances
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2024
·Vol. 10
·期 13
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IF 11.7
Qian Huang,Yi Ru,Yingli Luo,Xianyu Luo,Didi Liu,Yinchu Ma,Xinru Zhou,Maoyuan Linghu,Wen Xu,Fei Gao,Yi Huang
Ferroptosis is a form of iron-dependent, lipid peroxidation–driven regulatory cell death that has been implicated in the pathogenesis of multiple diseases, including organ injury, ischemia/reperfusion, and neurodegenerative diseases. However, inhibitors that directly and specifically target ferroptosis are not yet available. Here, we identify the compound AS-252424 (AS) as a potent ferroptosis inhibitor through kinase inhibitor library screening. Our results show that AS effectively inhibits lipid peroxidation and ferroptosis in both human and mouse cells. Mechanistically, AS directly binds to the glutamine 464 of ACSL4 to inhibit its enzymatic activity, resulting in the suppression of lipid peroxidation and ferroptosis. By using nanoparticle-based delivery systems, treatment with AS-loaded nanoparticles effectively alleviate ferroptosis-mediated organ injury in mouse models, including kidney ischemia/reperfusion injury and acute liver injury (ALI). Thus, our results identify that AS is a specific and targeted inhibitor of ACSL4 with remarkable antiferroptosis function, providing a potential therapeutic for ferroptosis-related diseases.
研究领域:
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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治疗学
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DOI
PubMed
高影响因子
Exploration
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2024
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IF 0
Xue Bai,Jun Kang,Silong Wei,Yun Wang,Yangsui Liu,Bo Yuan,Qian Lu,Huansong Li,Jun Yan,Xi Yang,Jin Chang
Sonodynamic therapy offers a non-invasive approach to induce the death of tumor cells. By harnessing ultrasound waves in tandem with sonosensitizers, this method produces reactive oxygen species (ROS) that inflict oxidative damage upon tumor cells, subsequently causing their demise. Ferroptosis is a regulatory form of cell death that differs from other forms, characterized by iron accumulation, ROS accumulation, and lipid peroxidation. In the presented research, a nanoparticle formulation, parthenolide/ICG-CaCO 3 @lipid (PTL/ICG-CaCO 3 @Lip), has been engineered to amplify ferroptosis in tumor cells, positioning it as a potent agent for sonodynamic cancer immunotherapy. This nanoparticle significantly augments ROS levels within tumor cells, inducing oxidative stress that leads to cell death. The therapeutic potential of PTL/ICG-CaCO 3 @Lip, both in vivo and in vitro, has been convincingly demonstrated. Furthermore, RNA-seq analysis insights revealed that PTL/ICG-CaCO 3 @Lip facilitates tumor cell ferroptosis by regulating P53 to downregulate SLC7A11 protein expression, thereby inhibiting the glutamate-cystine antiporter system Xc − and stimulating ACSL4/LPCAT3 pathways. This pioneering work uncovers an innovative strategy for combatting tumors, leveraging enhanced oxidative stress to promote cell ferroptosis, and paves the way for groundbreaking cancer immunotherapeutic interventions.
研究领域:
肿瘤学
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生物医学工程
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药理学
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分子生物学
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DOI
Journal of Diabetes Research
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2024
·Vol. 2024
·期 1
·7146054
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IF 3.6
Liangxiu Wu,Weicheng Lai,Lanlan Li,Sen Yang,Fengjuan Li,Chen Yang,Xiaobing Gong,Liangyan Wu
Background: Diabetic liver injury is a serious complication due to the lack of effective treatments and the unclear pathogenesis. Ferroptosis, a form of cell death involving reactive oxygen species (ROS)-dependent lipid peroxidation (LPO), is closely linked to autophagy and diabetic complications. Therefore, this study is aimed at investigating the role of autophagy in regulating ferroptosis by modulating the degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4) in diabetic hepatocytes and its potential impact on diabetic liver injury. Methods: Initially, ferroptosis and autophagy were assessed in liver tissues from streptozotocin-induced diabetic rats and in palmitic acid (PA)–treated LO2 cells. Subsequently, the study focused on elucidating the regulatory role of autophagy in mediating ferroptosis through the modulation of ACSL4 expression in PA-treated LO2 cells. Results: The results demonstrated that ACSL4-mediated ferroptosis and inhibition of autophagy were observed in diabetic hepatocytes in vivo and in PA-treated LO2 cells. Additionally, the ferroptosis inhibitor was able to mitigate the PA-induced cell death in LO2 cells. Mechanistically, the stability and expression level of the ACSL4 protein were upregulated and primarily degraded via the autophagy-lysosome pathway in PA-treated LO2 cells. The use of the autophagy inhibitor 3-methyladenine (3-MA) and the inducer rapamycin further demonstrated that autophagy regulated ferroptosis by mediating ACSL4 degradation, highlighting its critical role in diabetic liver injury. Conclusions: These results elucidate the roles of ferroptosis, autophagy, and their interactions in the pathogenesis of diabetic liver injury, offering potential therapeutic targets. Furthermore, they shed light on the pathogenesis of ferroptosis and other diabetic complications.
研究领域:
糖尿病
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肝病学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Feng Chen,Minghua Su,Dong Han,Yifan Wang,Menglong Song
Methyltransferase-like 14 (METTL14) is implicated in the regulation of various inflammatory disorders. However, its function and molecular mechanism in severe acute pancreatitis (SAP) remains unrevealed. Here we reported an increase in METTL14 in the pancreas of SAP mice and cerulein-LPS-treated AR42J cells. METTL14 depletion reversed inflammatory response and ferroptosis by reducing the expression of SAT1 (spermidine/spermine N1-acetyltransferase 1) and ACSL4 (acyl-CoA synthetase long chain family member 4) in an m6A-dependent manner. IGF2BP2 (insulin like growth factor 2 mRNA binding protein 2) could recognize m6A-modified SAT1 and ACSL4 mRNA and enhance their stability. Moreover, METTL14 depletion ameliorated pancreatic injury, inflammation, and ferroptosis induced by SAP. METTL14 overexpression aggravated SAP by promoting ferroptosis in vivo. Therefore, these results demonstrated that METTL14-induced ferroptosis promoted the progression of SAP, and targeting METTL14 or ferroptosis could be a potential strategy for the prevention and treatment of SAP.
研究领域:
分子生物学
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炎症性疾病
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胃肠病学
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DOI
PubMed
高影响因子
DRUG RESISTANCE UPDATES
·
2023
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IF 24.3
Ran Qi,Yixuan Bai,Kun Li,Nanbin Liu,Yan Xu,Emre Dal,Yufeng Wang,Rui Lin,Hui Wang,Zhongyan Liu,Xinbo Li,Xiuyan Wang,Baomin Shi
Background Pancreatic cancer continues to be one of the world's most lethal cancers. Chemotherapy resistance in patients with advanced pancreatic cancer often accompany with dismal prognosis, highlighting the need to investigate mechanisms of drug resistance and develop therapies to overcome chemoresistance. Methods This research was filed with the Chinese Clinical Trial Registry (ChiCTR2200061320). In order to isolate primary normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) samples of pancreatic ductal adenocarcinoma (PDAC) and paracancerous pancreatic tissue from individuals diagnosed with PDAC were obtained. The exosomes were obtained using ultracentrifugation, and their characteristics were determined by Western blotting, nanoparticle tracking analysis, and transmission electron microscopy. CAF-derived miRNAs were analyzed by RT-qPCR and high-throughput sequencing. Gemcitabine (GEM) was employed to promote ferroptosis, and ferroptosis levels were determined by monitoring lipid reactive oxygen species (ROS), cell survival, and intracellular Fe 2+ concentrations. To assess in vivo tumor response to GEM therapy, a xenograft tumor mouse model was utilized. Results Exosomes derived from CAFs in PDAC did not exhibit innate GEM resistance. CAFs promoted chemoresistance in PDAC cells following GEM treatment by secreting exosomes, and maintaining signaling communication with cancer cells. Mechanistically, miR-3173–5p derived from CAF exosomes sponged ACSL4 and inhibited ferroptosis after uptake by cancer cells. Conclusion This work demonstrates a novel mode of acquired chemoresistance in PDAC and identifies the miR-3173–5p/ACSL4 pathway as a promising treatment target for GEM-resistant pancreatic cancer.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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DOI
PubMed
高影响因子
JOURNAL OF ANIMAL SCIENCE
·
2024
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IF 2.7
Ma Zifeng,Li Qiao,Xu Hongmei,Li Yueyue,Wang Shujin,Xiong Yan,Lan Daoliang,Li Jian,Xiong Xianrong,Fu Wei
Zearalenone (ZEN), a mycotoxin from Fusarium fungi, impairs fertility and milk production in female animals, however, the mechanisms remain poorly understood. Using the bovine mammary epithelial cells (MAC-T) as the model, this study investigated the impacts of ZEN on programmed cell death (PCD) and milk fat synthesis, and explored the underlying mechanism. We found that 10 ng/mL prolactin (PRL) notably enhanced the differentiation of MAC-T cells, promoting the expression of genes related to the synthesis of milk fat, protein, and lactose. Next, the toxic effects of different doses of ZEN on the differentiated MAC-T with PRL treatment were determined. 10 μM and 20 μM ZEN significantly reduced cell viability, induced oxidative stress, and triggered PCD (e.g. apoptosis and necrosis). Notably, ZEN exposure downregulated the mRNA/protein levels of critical factors involving in milk fat synthesis by disrupting the AKT-mTOR-PPARγ-ACSL4 pathway. Interestingly, melatonin (MT), known for its antioxidant properties, protected against the above ZEN-induced effects by enhancing the binding of PPARγ to the promoter regions of ACSL4, which led to the upregulated expression of ACSL4 gene. These results underscored the potential of MT to mitigate the adverse effects of ZEN on mammary cells, highlighting a way for potential therapeutic intervention.
研究领域:
兽医学
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毒理学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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