BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2025
·Vol. 136
·期 5
·e70027
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IF 3.3
Mengjie Guo,Han Meng,Yi Sun,Lianxin Zhou,Tingting Hu,Tianyi Yu,Haowen Bai,Yuanjiao Zhang,Chunyan Gu,Ye Yang
Multiple myeloma (MM) is an incurable hematologic malignancy, driving significant interest in the discovery of novel therapeutic strategies. Bruceine A (BA), a tetracyclic triterpene quassinoid derived from Brucea javanica , has shown anticancer properties by modulating multiple intracellular signalling pathways and exhibiting various biological effects. However, the specific pharmacological mechanisms by which it combats MM remain unclear. In this study, we identified USP13 as a potential target of BA. We observed a significant increase in USP13 expression in patients with MM, which was strongly associated with a poorer prognosis. Furthermore, enhanced USP13 expression can stimulate MM cell proliferation both in vitro and in vivo. Mass spectrometry analysis, combined with co-immunoprecipitation and in vitro ubiquitination experiments, revealed PARP1 as a critical downstream target of USP13. USP13 can stabilize PARP1 protein through deubiquitination, promoting PARP1-mediated DNA damage repair (DDR) and facilitating MM progression. Notably, we utilized MM cell lines, an MM Patient-Derived Tumour Xenograft model, and a 5TMM3VT mouse model to determine the anticancer effects of BA on MM progression, revealing its potential to target USP13/PARP1 signalling and disrupt DDR in MM cells. In conclusion, these findings suggest that BA inhibiting USP13/PARP1-mediated DDR might be a promising therapeutic strategy for MM.
研究领域:
肿瘤学
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药理学
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分子生物学
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Frontiers in Cell and Developmental Biology
·
2021
·
IF 6.684
Xu Yifeng,Wang Boqian,Liu Xiaoxiao,Deng Yunfei,Zhu Yanqi,Zhu Feng,Liang Yanyan,Li Hongli
Myocardial ischemia–reperfusion injury (MIRI), characterized by post-ischemic cardiomyocytes death and reperfusion myocardial damage, is a lethal yet unresolved complication in the treatment of acute myocardial infarction (AMI). Previous studies have demonstrated that poly(ADP-ribose) polymerase-1 (PARP1) participates in the progression of various cardiovascular diseases, and various reports have proved that PARP1 can be a therapeutic target in these diseases, but whether it plays a role in MIRI is still unknown. Therefore, in this study, we aimed to explore the role and mechanism of PARP1 in the development of MIRI. Firstly, we demonstrated that PARP1 was activated during MIRI-induced myocardial autophagy in vitro. Moreover, PARP1 inhibition protected cardiomyocytes from MIRI through the inhibition of autophagy. Next, we discovered that specificity protein1 (Sp1), as a transcription factor of PARP1, regulates its target gene PARP1 through binding to its target gene promoter during transcription. Furthermore, silencing Sp1 protected cardiomyocytes from MIRI via the inhibition of PARP1. Finally, the functions and mechanisms of PARP1 in the development of MIRI were also verified in vivo with SD rats model. Based on these findings, we concluded that PARP1 inhibition protects cardiomyocytes from MIRI through the inhibition of autophagy, which is targeted by Sp1 suppression. Therefore, the utilization of PARP1 exhibits great therapeutic potential for MIRI treatment in future.
研究领域:
心血管疾病
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分子生物学
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药理学
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Cell Death & Disease
·
2024
·Vol. 15
·期 12
·1-14
·
IF 8.1
Chen Li,Zou Yahui,Sun Renhong,Huang Mei,Zhu Xiaotong,Tang Xiao,Yang Xiaobao,Li Dake,Fan Gaofeng,Wang Yu
Poly (ADP-ribose) polymerase 1 (PARP1) catalyzes poly (ADP) ribosylation reaction, one of the essential post-translational modifications of proteins in eukaryotic cells. Given that PARP1 inhibition can lead to synthetic lethality in cells with compromised homologous recombination, this enzyme has been identified as a potent target for anti-cancer therapeutics. However, the clinical application of existing PARP1 inhibitors is restrained by side effects associated with DNA trapping and off-target effects, highlighting the need for improved therapeutic strategies. By integrating protein degradation technology, we synthesized a PROTAC molecule 180055 based on the Rucaparib junction and VHL ligand, which efficiently and selectively degraded PARP1 and inhibited PARP1 enzyme activity without a noticeable DNA trapping effect. Furthermore, 180055 kills tumor cells carrying BRCA mutations with a minor impact on the growth of normal cells both in vitro and in vivo. This suggests that 180055 is a PARP1-degrading compound with excellent pharmacological efficacy and extremely high biological safety that deserves further exploration and validation in clinical trials.
研究领域:
肿瘤学
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分子生物学
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药理学
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癌症研究
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CELL DEATH AND DIFFERENTIATION
·
2024
·
IF 13.7
Yang Jing,Wan Shi-yuan,Song Qiu-yi,Xie Yun-hao,Wan Jun,Zhou Yi-hao,Zhang Zi-tong,Xiao Yu-shuo,Li Xi,Chen Hong,Liu Xin-ran,Xu Li,You Hui-juan,Hu De-sheng,Petersen Robert B.,Zhang Yong-hui,Zheng Ling,Zhang Yu,Huang Kun
Upon genotoxic stresses, cells employ various DNA damage responses (DDRs), including DNA damage repair or apoptosis, to safeguard genome integrity. However, the determinants among different DDRs choices are largely unknown. Here, we report angiopoietin-like protein 8 (ANGPTL8), a secreted regulator of lipid metabolism, localizes to the nucleus and acts as a dynamic switch that directs DDRs towards apoptosis rather than DNA repair after genotoxin exposure. ANGPTL8 deficiency alleviates DNA damage and apoptosis in cells exposed to genotoxins, as well as in the liver or kidney of mice injured by hepatic ischemia/reperfusion or cisplatin treatment. Mechanistically, ANGPTL8 physically interacts with Poly (ADP-ribose) polymerase 1 (PARP1), in a PARylation-independent manner, and reduces the fluidity of PARP1-DNA condensates, thereby enhancing the pro-apoptotic accumulation of PARP1 and PAR chains on DNA lesions. However, the transcription of ANGPTL8 is gradually decreased following genotoxin treatment, partly due to downregulation of CCAAT enhancer binding protein alpha (CEBPA), presumably to avoid further cytotoxicity. Together, we provide new insights by which genotoxic stress induced DDRs are channeled to suicidal apoptosis to safeguard genome integrity.
研究领域:
癌症生物学
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分子遗传学
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细胞生物学
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PHYTOMEDICINE
·
2024
·
IF 6.7
Jinhai Lin,Xiaolong Wang,Mingyang Gu,Yuanyuan Chen,Jiongbo Xu,Nhi Van Chau,Junlong Li,Xiaodong Ji,Qingmin Chu,Lijin Qing,Wei Wu
Background Atherosclerosis (AS) is the leading cause of global death, which manifests as arterial lipid stack and plaque formation. Geniposide is an iridoid glycoside extract from Gardenia jasminoides J.Ellis that ameliorates AS by mediating autophagy. However, how Geniposide regulates autophagy and treats AS remains unclear. Purpose To evaluate the efficacy and mechanism of Geniposide in treating AS. Study design and methods: Geniposide was administered to high-fat diet-fed ApoE −/− mice and oxidized low-density lipoprotein-incubated primary vascular smooth muscle cells (VSMCs). AS was evaluated with arterial lipid stack, plaque progression, and collagen loss in the artery. Foam cell formation was detected by lipid accumulation, inflammation, apoptosis, and the expression of foam cell markers. The mechanism of Geniposide in treating AS was assessed using network pharmacology. Lipophagy was measured by lysosomal activity, expression of lipophagy markers, and the co-localization of lipids and lipophagy markers. The effects of lipophagy were blocked using Chloroquine. The role of PARP1 was assessed by Olaparib (a PARP1 inhibitor) intervention and PARP1 overexpression. Results In vivo , Geniposide reversed high-fat diet-induced hyperlipidemia, plaque progression, and inflammation. In vitro , Geniposide inhibited VSMC-derived foam cell formation by suppressing lipid stack, apoptosis, and the expressions of foam cell markers. Network pharmacological analysis and in vitro validation suggested that Geniposide treated AS by enhancing lipophagy via suppressing the PI3K/AKT signaling pathway. The benefits of Geniposide in alleviating AS were offset by Chloroquine in vivo and in vitro . Inhibiting PARP1 using Olaparib promoted lipophagy and alleviated AS progression, while PARP1 overexpression exacerbated foam cell formation and lipophagy blockage. The above effects of PARP1 were weakened by PI3K inhibitor LY294002. PARP1 also inhibited the combination of the ABCG1 and PLIN1. Conclusion Geniposide alleviated AS by restoring PARP1/PI3K/AKT signaling pathway-suppressed lipophagy. This study is the first to present the lipophagy-inducing effect of Geniposide and the binding of ABCG1 and PLIN1 inhibited by PARP1.
研究领域:
心血管疾病
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药理学
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分子生物学
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细胞生物学
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高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 6.7
Xinxin Li,Cheng Wang,Shang Li,Fucheng Yin,Heng Luo,Yonglei Zhang,Zhongwen Luo,Yifan Chen,Siyuan Wan,Lingyi Kong,Xiaobing Wang
Currently available PARP inhibitors are mainly used for the treatment of BRCA-mutated triple-negative breast cancer (TNBC), with a narrow application range of approximately 15% of patients. Recent studies have shown that EZH2 inhibitors have an obvious effect on breast cancer xenograft models and can promote the sensitivity of ovarian cancer cells to PARP inhibitors. Here, a series of new dual-target PARP1/EZH2 inhibitors for wild-BRCA type TNBC were designed and synthesized. SAR studies helped us identify compound 12e , encoded KWLX-12e , with good inhibitory activity against PARP1 (IC 50 = 6.89 nM) and EZH2 (IC 50 = 27.34 nM). Meanwhile, KWLX-12e showed an optimal cytotoxicity against MDA-MB-231 cells (IC 50 = 2.84 μM) and BT-549 cells (IC 50 = 0.91 μM), with no toxicity on normal breast cell lines. KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI = 57.24%). Mechanistic studies showed that KWLX-12e achieved synthetic lethality indirectly by inhibiting EZH2 to increase the sensitivity to PARP1, and induced cell death by regulating excessive autophagy. KWLX-12e is expected to be a potential candidate for the treatment of TNBC.
研究领域:
肿瘤学
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药理学
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癌症生物学
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分子生物学
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高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
·
2025
·Vol. 30
·期 1
·1-27
·
IF 10.2
Chen Dejian,Xie Fei,Mo Yimei,Qin Dan,Zheng Binjiao,Chen Lingyan
Background The classical ferroptosis activator RSL3 targets enzymes with nucleophilic active sites, primarily acting on glutathione peroxidase 4 (GPX4) to trigger ferroptosis. Recent studies identify RSL3 as a potential pro-apoptotic agent. However, the mechanism by which RSL3 induces apoptosis during ferroptosis remains elusive. Poly(ADP-ribose) polymerase (PARP1) determines cell fate in response to DNA damage, where its loss or cleavage by activated caspase-3 induces apoptosis to attenuate tumor progression. We elucidate a novel mechanism underlying PARP1 regulation, encompassing both its caspase-dependent cleavage and full-length depletion during RSL3-mediated ferroptosis-apoptosis crosstalk. Methods To investigate the role of RSL3 during ferroptosis, we treated several cancer cells of different histological types with varying doses of RSL3 to induce apoptosis. The regulatory proteins of PARP1 were analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The N 6 -methyladenosine (m 6 A) modification level of PARP1 was determined by m 6 A RNA immunoprecipitation (MeRIP)-qPCR analysis. Additionally, an RNA immunoprecipitation (RIP)-qPCR assay was performed to identify the target protein of the m 6 A site of PARP1. Furthermore, we established a mouse xenograft model of PARP inhibitor (PARPi)-resistant cells to analyze the effect of RSL3 on PARPi-resistant tumor growth. Results RSL3 triggers two parallel apoptotic pathways via increasing reactive oxygen species (ROS) production during ferroptosis: (1) caspase-dependent PARP1 cleavage and (2) DNA damage-dependent apoptosis resulting from reduced full-length PARP1. The latter occurs through inhibition of METTL3-mediated m 6 A modification and subsequent suppression of PARP1 translation. Moreover, we found that RSL3 retains pro-apoptotic functions in PARPi-resistant cells and effectively inhibits PARPi-resistant xenograft tumor growth in vivo. Conclusions RSL3 orchestrates ferroptosis-apoptosis crosstalk via PARP1, demonstrating therapeutic potential against tumorigenesis, particularly in PARPi-resistant malignancies. Graphical
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JOURNAL OF CELL BIOLOGY
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2025
·Vol. 225
·期 1
·e202501091
·
IF 6.4
Gao Kun,Shi Ruiya,Xu Chenying,Mao Zhaoyang,Guo Changying,Jin Liang
DNA damage repair is vital for maintaining genetic stability and integrity of cells that encounter DNA-damaging agents. So far, a series of multifunctional proteins and long noncoding RNAs (lncRNAs) have been demonstrated to participate in the DNA damage response (DDR). However, our current understanding of detailed mechanisms of DNA damage repair remains limited. Herein, we report that lncRNA EGFR-AS1 is functionally involved in DDR in both non–small-cell lung cancer cells and noncancerous cells. Using DNA repair reporter, we found that EGFR-AS1 overexpression significantly enhances the efficiency of both the classical nonhomologous end-joining and homologous recombination pathways. Through the lncRNA interactome, we identified a set of DNA repair factors, including the canonical DNA damage sensor PARP1 and NAD+ supplier NMNAT1. Upon DNA damage, DNA-activated PARP1 binds to EGFR-AS1 and forms a ternary complex with NMNAT1, promoting NAD+ utilization and poly(ADP-ribosyl)ation (PARylation) of PARP1. Additionally, EGFR-AS1 also facilitates displacing PARP1 from the sites of damaged DNA. Our findings demonstrate a lncRNA-associated PARP1 activation and displacement in DDR and highlight the potential of EGFR-AS1 as a target for cancer therapy.
研究领域:
分子生物学
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肿瘤学
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遗传学
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细胞生物学
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转化医学
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JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·Vol. 69
·期 15
·19402-19420
·
IF 7.3
Wang Wenchao,Li Dan,Liu Jin,Li Lei,Zhang Qi,Zhang Facai,Liu Yang,Zhang Yifan,Meng Shuai,Shi Xuyang,Wang Hong,Li Qingyong,Zhang Dahong,Mao Zujie
Bladder
cancer is a malignant tumor with a high incidence and mortality
worldwide. Clinically, DNA-damaging agents such as cisplatin, irinotecan,
and gemcitabine are commonly used, but their efficacy is often limited
by acquired resistance. A key resistance mechanism involves the upregulation
of PARP1 in response to drug-induced DNA single-strand breaks (SSBs),
which diminishes the therapeutic effect. To overcome this obstacle,
we designed and synthesized a series of united TOP1/PARP1 inhibitors
that simultaneously induce SSBs via TOP1 inhibition and block their
repair via PARP1 inhibition, converting repairable SSBs to lethal
double-strand breaks (DSBs). Among these, compound D5 exhibited excellent dual-target inhibitory activity and effectively
overcame cisplatin resistance, demonstrating potent antitumor efficacy in vitro and in vivo (TGI = 65.7%). Collectively, D5 represents a promising TOP1/PARP1 inhibitor for overcoming
resistance to conventional DNA-damaging chemotherapies.
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JOURNAL OF HAZARDOUS MATERIALS
·
2025
·
IF 11.3
Nan Zhao,Wei Song,Tianshu Sun,Weiwei Wu,Yongliang Feng,Ning Ma,Suping Wang
Prenatal exposure to Benzo[ a ]pyrene (BaP) has been shown to increase the risk of adverse birth outcomes, potentially through disruption of maternal metabolic homeostasis. However, the underlying pathways and mechanisms remain unclear. To address this knowledge gap, we employed a multi-omics approach combining experimental and epidemiological investigations. In the mouse model, untargeted metabolomics profiling revealed niacinamide (NAM) metabolism as the most significantly altered pathway in both maternal serum and placenta following BaP exposure. Mechanistically, BaP exposure reduced nicotinamide adenine dinucleotide (NAD+) synthesis while increasing its catabolism through activation of poly (ADP-ribose) polymerase 1 (PARP1) in placental tissue. Subsequent transcriptomic analysis showed that BaP-induced NAD+ depletion led to sirtuin 1 (SIRT1) suppression and consequent exacerbation of the NF-κB-mediated inflammatory response. These experimental findings were substantiated in human populations through targeted metabolomic analysis of a Chinese birth cohort, where significant NAM metabolic disturbances were observed in women with high BaP exposure experiencing preterm delivery. Our study provides novel mechanistic evidence that BaP-induced dysregulation of NAM metabolism mediates adverse birth outcomes through NAD+ deficiency and subsequent inflammatory response. These findings not only identify potential therapeutic targets but also highlight the urgent need for evidence-based environmental policy interventions and nutritional supplementation strategies to protect maternal-fetal health in high-risk populations.
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Autophagy
·
2026
·
IF 18.6
Yiping Shi,Long Chen,Yuxiao Feng,Jingtao Liu,Wendi Wu,Yawei Jin,Huan Tong,Yijie Huang,Yiming Li,Zhaokuan Li,Guo Zhou,Ben He,Yu Wang,Qin Shao
Doxorubicin is a widely used chemotherapeutic agent, but its clinical application is hindered by severe cardiotoxicity. Among immune cells, Cx3cr1+ macrophages have emerged as key regulators of cardiovascular disease, with their development and maturation tightly controlled by CSF1R (colony stimulating factor 1 receptor). Using multi-omics sequencing, we observed a marked expansion of Cx3cr1+ macrophages in doxorubicin-induced cardiomyopathy, yet their precise functional role in this pathological process has remained elusive. This study employed various genetically modified mouse models, including cell depletion models, lineage tracing models, and conditional gene knockout models targeting Cx3cr1+ macrophages, alongside transcriptomic sequencing, proteomic profiling, and multi-level in vivo and in vitro experiments to elucidate the role and mechanisms of Cx3cr1+ macrophages and their receptor CSF1R in doxorubicin-induced cardiac injury. We found that Cx3cr1+ macrophages are significantly enriched in hearts affected by doxorubicin-induced cardiomyopathy, and their depletion notably improves cardiac function. Further investigation revealed that in these macrophages, CSF1R competitively binds to the E3 ubiquitin ligase NEDD4, thereby inhibiting the ubiquitination and degradation of PARP1. This process promotes inflammasome activation and pyroptosis, driving massive IL1B secretion. IL1B directly suppresses cardiomyocyte mitophagy, disrupts energy metabolic homeostasis, and ultimately leads to cardiac dysfunction. Notably, the use of the CSF1R inhibitor PLX3397 or an IL1B-neutralizing antibody effectively halted these pathological processes and significantly improved cardiac function. In summary, this study unveils a novel mechanism through which Cx3cr1+ macrophages regulate cardiomyocyte function via the CSF1R-PARP1-IL1B-mitophagy signaling axis, providing a new theoretical foundation and intervention strategy for doxorubicin-induced cardiomyopathy targeted therapy.Abbreviations: BMDM: bone marrow-derived macrophages; CKMB: creatine kinase MB isoenzyme; CSF1R: colony stimulating factor 1 receptor; csf1r-cKO: csf1r conditional knockout; DIC: doxorubicin-induced cardiomyopathy; DOX: doxorubicin; HE: hematoxylin and eosin; HW:TL: heart weight:tibial length; LDH: lactate dehydrogenase; MAP1LC3/LC3: microtuble-associated protein 1 light chain 3; NPPA: natriuretic peptide type A; PI: propidium iodide; PYCARD/ASC: PYD and CARD domain containing; TNNT2/cTnT: troponin T2, cardiac; WGA: wheat germ agglutinin.
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iScience
·
2024
·
IF 4.6
Yixiao Li,Yuhan Jiang,Haoyi Yan,Ziheng Qin,Yidi Peng,Danyu Lv,Hongquan Zhang
Histone lysine isonicotinylation (Kinic) induced by isoniazid (INH) was recently identified as a post-translational modification in cells. However, global cellular non-histone proteins Kinic remains unclear. Using proteomic technology, we identified 11,442 Kinic sites across 2,792 proteins and demonstrated that Kinic of non-histone proteins is involved in multiple function pathways. Non-histone proteins Kinic can be regulated by isonicotinyl-transferases, including CBP and Tip60, and deisonicotinylases, including HDAC8 and HDAC6. In particular, the Kinic of poly (ADP-ribose) (PAR) polymerase 1 (PARP1) can be catalyzed by CBP and deisonicotinylation can be catalyzed by HDAC8. Tip60 and HDAC6 are isonicotinyl-transferase and the deisonicotinylase of SMAD3, respectively. Importantly, we found the K378inic of SMAD3 increases its phosphorylation, activates TGFβ pathway, and promotes liver cancer cells migration and invasion. In conclusion, our study demonstrated non-histone proteins Kinic occur extensively in cells and plays an important role in regulation of various cellular functions, including cancer progression.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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蛋白质组学
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PubMed
高影响因子
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