ENVIRONMENTAL POLLUTION
·
2025
·
IF 7.3
Ziyuan Li,Pu Chen,Yongfeng Lin,Jingxu Zhang,Jian Ding,Rifat Zubair Ahmed,Xiaoting Jin,Yuxin Zheng
Tris (2-chloroethyl) phosphate (TCEP), recognized as an emerging pollutant, has been frequently detected in human blood. Maintenance of blood homeostasis is indispensable for regulating various physiological states and overall health, yet hematological toxicology of TCEP has not been extensively investigated. Platelets, a vital component of blood, are fundamental in the processes of hemostasis and thrombosis through their activation; thus, this study was designed to elucidate the effects and underlying mechanisms of TCEP on platelet activation. Utilizing an in vivo model, we conducted a proteomic analysis of platelets and found that TCEP exposure inhibited platelet activation. An ex vivo platelet evaluation system was employed to further dissect the processes of platelet activation, revealing that TCEP predominantly suppressed platelet aggregation, degranulation and clot retraction. These processes were highly dependent on energy metabolism, and TCEP was found to decrease ATP levels, primarily by impairing glycolysis and pentose phosphate pathways. Subsequent investigation into the molecular mechanisms revealed that TCEP decreased the activity of phosphofructokinase platelet (PFKP) by enhancing O-linked N-acetylglucosamine (O-GlcNAc) transferase interaction with PFKP. This study is the first to uncover the disruptive effects of TCEP on platelet activation process, providing valuable insights into the assessment of hematologic health risks associated with TCEP-like emerging pollutants exposure.
研究领域:
血液学
·
毒理学
·
分子生物学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NUCLEIC ACIDS RESEARCH
·
2026
·Vol. 54
·期 7
·gkag336
·
IF 15
Haoyun Liu,Ming Zhang,Zhanzhan Xu,Zexin Yang,Yichen Pan,Yongtai Bai,Xinhui Zhao,Weibin Wang,Yang Yang,Jiadong Wang
Emerging evidence suggests a critical interplay between glycolysis and DNA damage repair (DDR) during tumor progression. However, the precise molecular mechanisms coordinating these processes remain unclear. This study reveals a previously unrecognized role of the platelet isoform of phosphofructokinase-1 (PFKP) in homologous recombination (HR) repair. Our investigations demonstrated that ataxia-telangiectasia mutated (ATM) kinase phosphorylates PFKP at residue T278, promoting its transition from tetramers to dimers in response to ionizing radiation (IR) and high glucose (HG) stimulation. The nuclear localized dimeric PFKP recruits casein kinase 2 (CK2), which subsequently phosphorylates RAD51 at residue T13, thereby enhancing the RAD51-BRCA2 interaction and HR efficiency. Clinically, PFKP exhibits significant nuclear accumulation in diabetes-associated malignancies. Importantly, simultaneous targeting of glycolysis and the HR pathway increases tumor sensitivity to radiotherapy. These findings elucidate the pivotal role of PFKP as a metabolic molecular switch that balances glycolysis and DDR, offering new perspectives for the development of metabolically targeted anticancer strategies.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ONCOGENE
·
2020
·Vol. 39
·期 11
·2408-2423
·
IF 7.971
Guan Yun-feng,Huang Qiao-ling,Ai Yuan-li,Chen Qi-tao,Zhao Wen-xiu,Wang Xiao-min,Wu Qiao,Chen Hang-zi
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）