BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2019
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IF 2.705
Ning Wang,Guang-Zhi Zeng,Jun-Lin Yin,Zhao-Xiang Bian
Currently, there is no effective treatment for Burkitt's lymphoma in patients aged above 60 years, and thus research on effective treatment options for Burkitt's lymphoma has been gaining increasing attention. Artesunate has been identified as a novel effective growth suppressor in Burkitt's lymphoma. Here, we utilized molecular biology , transcriptome analysis , and other techniques to study artesunate-induced death of the Burkitt's lymphoma cells DAUDI and CA-46, the effect of artesunate on gene expression in DAUDI and CA-46 cells, and the effect of artesunate-induced ATF4-CHOP-CHAC1 pathway on ferroptosis . We also studied the inhibitory effects and ferroptosis induction of artesunate on CA-46 cells in mouse xenografts. Results showed that artesunate induced ferroptosis in DAUDI and CA-46 cells, as evidenced by the protective effect of liproxstatin-1, ferrostatin-1, and desferoxamine, resulting in an endoplasmic reticulum stress response, a ctivation of the ATF4-CHOP-CHAC1 pathway enhanced ferroptosis in DAUDI and CA-46 cells. A mouse-transplanted tumor model showed that artesunate can inhibit the proliferation and induce ferroptosis of CA-46 cells in vivo . This study provides a novel perspective for the development of drugs against different types of Burkitt's lymphomas.
研究领域:
肿瘤学
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分子生物学
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转录组学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2026
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IF 6.6
Yannan Gu,Yajun Shi,Bin Wei,Yan Zhao,Ming Huo,Li Zeng,Zejun Zhao,Yueyang Song,Xi Yu,Youguo Chen,Miao Sun
Fluoride exposure is linked to impaired reproductive capacity in female mammals. Ovarian reserve is established during fetal development. Maternal exposure to adverse environmental factors during pregnancy can impair offspring ovarian function, with prenatal fluoride exposure potentially contributing to ovarian dysfunction, though underlying mechanisms remain unclear. We established a model with C57BL/6 J mice that were given 100 mg/L sodium fluoride (NaF) from the 1st day of pregnancy to the 20th day. NaF exposure impaired ovarian function in female offspring, manifested as reduced ovarian reserve, disrupted follicular maturation, and increased follicular atresia. Molecular analyses demonstrated elevated ATF4 expression, decreased SIRT1 levels, upregulated CHOP, and activation of the BAX/BCL-2 apoptotic pathway in offspring ovaries, indicating ovarian apoptosis as the primary mechanism of ovarian dysfunction. Chromatin immunoprecipitation (ChIP) revealed that NaF exposure increased H3K9ac binding at the Atf4 promoter region, suggesting SIRT1-mediated regulation enhances - Atf4 acetylation and transcription. Consistently, NaF-treated KGN cells showed reduced SIRT1 and increased ATF4. Critically, resveratrol, a specific SIRT1 activator, effectively upregulated SIRT1 expression in both fluoride-exposed animal models and KGN cells. This intervention ameliorated ovarian dysfunction phenotypes and inhibited granulosa cell apoptosis. These results establish SIRT1-ATF4 signaling as the mechanistic core of fluoride-induced ovotoxicity and validate its targeting with Resveratrol as a therapeutic strategy against environmental ovarian dysfunction.
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TISSUE & CELL
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2026
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IF 3.1
Chen Chen,Qin Yu,Chen Xi,Minjuan Xie,Yinjie Jiang,Jie Zhou
Norcantharidin (NCTD) induces nephrotoxicity via mitochondria-dependent apoptosis. • The nephrotoxicity of NCTD involves inhibition of the ATF4/CTH/H 2 S pathway. • NCTD suppresses ATF4-driven CTH expression, reducing H 2 S production. • NCTD reduces H 2 S, impairing Drp1 S-sulfhydration and mitochondrial function. • ATF4, CTH, and H 2 S are potential therapeutic targets for NCTD-induced kidney injury. Norcantharidin serves as a therapeutic agent in the clinical care of malignant neoplasms. However, recent safety alerts issued in China in June 2025 highlighted its association with renal injury. Given that the mechanisms underlying NCTD-induced nephrotoxicity have yet to be completely defined, this work was designed to explore the impact of the ATF4/CTH/H 2 S pathway on nephrotoxicity triggered by NCTD. Our data revealed that exposure to NCTD triggered mitochondria-dependent apoptosis in renal cells, alongside decreased H 2 S levels, ROS accumulation, compromised mitochondrial integrity, and caspase-3 activation. Mechanistically, NCTD inhibited both ATF4 protein levels and its transcriptional function, resulting in downregulation of CTH and a subsequent reduction in H 2 S production. H 2 S deficiency impaired S-sulfhydration of Drp1, enhanced the Drp1-VDAC1 interaction, promoted mPTP opening, and ultimately triggered apoptosis. H 2 S supplementation rescued these defects by restoring Drp1 S-sulfhydration, but this protective effect was completely abolished by DTT, confirming the specificity of S-sulfhydration. Furthermore, overexpression of ATF4 or CTH alleviated NCTD-triggered apoptosis via H 2 S restoration, whereas knockdown of ATF4 or CTH exacerbated cytotoxicity. Critically, CTH knockdown abolished the protective effect of ATF4 overexpression, while CTH overexpression remained functional independently of ATF4. In conclusion, our findings established that NCTD induced nephrotoxicity primarily through the inhibition of the ATF4/CTH/H 2 S axis, which disrupted Drp1-mediated mitochondrial homeostasis. These results identified H 2 S restoration as a promising therapeutic strategy to mitigate NCTD-induced kidney injury.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2018
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IF 3.974
Peng Chen,Na Geng,Dong Zhou,Yiran Zhu,Yuliang Xu,Kangping Liu,Yongxia Liu,Jianzhu Liu
Hexavalent chromium (Cr(VI)) is a common environmental pollutant. Exposure of Cr(VI) can lead to cell autophagy, but the preventive measures for diminishing Cr(VI)-induced autophagy need further study. COX-2 can be induced by several heavy metals and can lead to endoplasmic reticulum (ER) stress and autophagy; thus, COX-2, ER stress, and autophagy may be related. This study mainly investigated the role of COX-2 in the eIF2α-ATF4 pathway, which is a major pathway in cell autophagy. In this study, Cr(VI) was used as a xenobiotic to determine changes in the parameters of ER stress, autophagy, and COX-2 levels. At the same time, a clear contrast was obtained by assigning positive and negative controls of ER stress and autophagy. The results showed that during Cr(VI) invasion, the parameters of ER stress and autophagy (such as BiP, PERK, p62, LC3-II, and mTOR) were enhanced, similarly to the positive control of ER stress and/or the autophagy controls. Such enhancement is a protective mechanism for cell survival. Additionally, the COX-2 levels increased. Moreover, when COX-2 was inhibited, the PERK level remained high, whereas the LC3-II level decreased. This finding suggests that COX-2 specifically affects the interaction between ER stress and autophagy. Notably, this study reveals that Cr(VI) can induce ER stress and autophagy in DF-1 cells and that COX-2 plays an essential role in the interaction between ER stress and autophagy.
研究领域:
毒理学
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细胞生物学
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环境科学
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TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Xin Zheng,Wei Wu,Yurou Li,Wupei Pan,Yinan Xu,Lianwei Zhong,Yinjie Jiang,Jie Zhou
Matrine (MT), an alkaloid extracted from Sophora flavescens , is widely used in traditional Chinese medicine. However, its clinical application is limited by its toxic effects. In this study, we explored the function of the activating transcription factor 4 /cystathionine γ-lyase (ATF4/CTH) pathway in MT-induced cardiac injury. Our results indicated that MT significantly decreased cysteine (Cys) and glutathione (GSH) levels, leading to mitochondrial dysfunction and apoptosis characterised by ROS accumulation, mPTP opening, ΔΨm disruption, and caspase-9/3 activation. However, caspase-3 inhibition and GSH supplementation alleviated these toxic effects. NAC similarly protected against MT-induced apoptosis by providing Cys as a substrate for GSH synthesis, whereas BSO abolished this protection by inhibiting GSH biosynthesis. Additionally, MT suppressed both ATF4 expression and its transcriptional activity, leading to reduced mRNA and protein levels of the downstream target gene CTH, and consequently diminished CTH-dependent Cys production. Overexpression of either ATF4 or CTH attenuated MT-induced apoptosis by restoring intracellular Cys and GSH levels. CTH knock-down completely abrogated the protective effects of ATF4 overexpression, whereas CTH overexpression retained its efficacy, even in the absence of ATF4. These results indicated that MT-induced suppression of the ATF4/CTH pathway causes GSH deficiency, leading to mitochondria-dependent apoptosis and cardiotoxicity.
研究领域:
毒理学
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分子生物学
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心血管研究
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药理学
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生物化学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2026
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IF 6.7
Boyu Huang,Ziyi Zhang,Junnan Shen,Weijun Pang
Lipid content in myofibers plays an important role in improving pork quality closely linked to flavor, tenderness, and marbling; however, the molecular mechanisms regulating lipid deposition in myofibers remain elusive. Here, we identify GA-binding protein α (GABPα) as a previously unrecognized transcriptional regulator (TF) of lipid deposition in porcine skeletal myofibers. Functional analyses show that GABPα markedly enhances lipid deposition in myofibers and activates endoplasmic reticulum (ER) stress in skeletal muscle. Mechanistically, GABPα directly binds to the promoter of the ER stress-associated gene activating transcription factor 4 (ATF4), thereby promoting lipid deposition in myofibers. Our findings establish GABPα as a novel key regulator of lipid deposition in myofibers and identify the GABPα–ATF4 regulatory axis as a mechanistic pathway connecting ER stress with porcine myofiber lipid deposition, providing significant implications to boost pork quality in the pig industry.
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BIOCHEMICAL PHARMACOLOGY
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2022
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IF 6.1
Yi Li,Wenyan She,Tangxi Guo,Tianhe Huang,Yixin liu,Pan Liu,Xiaoran Xu,Xinyu Wang,Miao Wang,Chaochao Yu,Yi Liu,Yongchang Wei
Developing novel drugs for gastric cancer (GC) is greatly needed, and a reactive oxygen species (ROS)-modulating strategy has been demonstrated to be useful for cancer treatment. However, no organic arsenical-derived ROS-modulating drug has been developed in GC. Here, we constructed ACZ2 and investigated its efficacy and potential mechanism for GC in vitro and in vivo. Our data showed that ACZ2 could inhibit GC proliferation and cause G2/M phase arrest. Moreover, ACZ2 induced ROS accumulation by depleting glutathione (GSH) and TrxR1, triggering a subsequent ER stress response by activating the PERK/EIF2/ATF4/CHOP signalling pathways, which is a crucial step for ACZ2-mediated apoptosis and autophagy. Vitally, ROS scavenger (NAC) and ER stress inhibitor (4PBA) reversed ACZ2/ROS/ER stress-mediated apoptosis and autophagy. Our in vivo results clearly demonstrated that ACZ2 suppressed tumour growth in a GC xenograft model. Collectively, our data indicated that ACZ2 is a potential agent against GC.
研究领域:
肿瘤学
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药理学
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细胞生物学
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Zexin Li,Xiao Wang,Yuanyuan Cui,Rui Wei,Yixin Wang,Yi Liu,Lifang Li,Jiasai Li,Liangbin Li,Keqiang Zuo
Macrophage-mediated inflammatory response is a critical pathogenic component in hepatic ischemia/reperfusion injury (HIRI) development. Although FOS-like antigen 2 (FOSL2) plays a pivotal role in regulating macrophage polarization, its role and potential mechanisms in HIRI remain unclear. The findings demonstrated that FOSL2 exhibited elevated expression levels in both the liver tissues and macrophages of the liver tissues in IR rats. Knockdown of FOSL2 significantly alleviated HIRI-induced liver injury, accompanied by the suppression of hepatic tissue apoptosis and oxidative stress. Furthermore, FOSL2 knockdown led to a reduction in the pro-inflammatory M1 phenotype and an increase in the anti-inflammatory M2 phenotype of Kupffer cells (KCs). Concomitantly, FOSL2 expression was markedly upregulated in KCs following lipopolysaccharide (LPS) stimulation, and FOSL2 silencing potently promoted the phenotypic switch of KCs from the pro-inflammatory M1 to the anti-inflammatory M2 state. Additionally, knockdown of FOSL2 in KCs attenuated KC-induced hepatocyte apoptosis and oxidative stress. Transcriptomic analysis conducted on liver tissues from HIRI rats with or without FOSL2 knockdown identified a significant downregulation of activating transcription factor 4 (ATF4), with a log2 fold change of −1.51 and a p-value < 0.05. Mechanistically, FOSL2 bound to the promoter region of ATF4 to drive its transcription, and ATF4 overexpression abrogated the phenotypic and functional effects elicited by FOSL2 silencing. Collectively, our findings illustrate that FOSL2 knockdown exerts a protective role against IR-induced hepatic stress, highlighting the importance of FOSL2 as a potential therapeutic target for HIRI.
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ACTA PHARMACOLOGICA SINICA
·
2023
·
IF 8.2
Zhang Zi-jian,Wu Qi-fang,Ren An-qi,Chen Qian,Shi Jiang-zhou,Li Jia-peng,Liu Xi-yu,Zhang Zhi-jie,Tang Yu-zhe,Zhao Yuan,Yao Ning-ning,Zhang Xiao-yu,Liu Chang-peng,Dong Ge,Zhao Jia-xuan,Xu Mei-jun,Yue Yun-qiang,Hu Jia,Sun Fan,Liu Yu,Ao Qi-lin,Zhou Fu-ling,Wu Hong,Zhang Tong-cun,Zhu Hai-chuan
Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS , ASS1 , PHGDH and SLC1A5 , maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti-leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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细胞信号传导
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PubMed
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ACTA PHARMACOLOGICA SINICA
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2020
·Vol. 42
·期 2
·290-300
·
IF 5.064
Yu Xiao-xuan,Zhu Meng-yuan,Wang Jia-rong,Li Hui,Hu Po,Qing Ying-jie,Wang Xiang-yuan,Wang Hong-zheng,Wang Zhan-yu,Xu Jing-yan,Guo Qing-long,Hui Hui
Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1–25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC 50 values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP 3 R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK–eIF2α–ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP 3 R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.2
Jiaqi Li,Zhengxin Lu,Nan Zhang,Xiaowei Zhou,Yuanbiao Ma,Jia-qi Li,Yimu Zhang,Zhewen Deng,Na Lin,Peng Yue,Yilin Yang,Qi Zhang,Bo Ma
Andrographolide (Andro), the primary bioactive compound of Andrographis paniculata , has known bioactivities but also male reproductive toxicity with unclear mechanisms. This study investigated its testicular injury effects and mechanism, focusing on Sertoli cells (SCs) ferroptosis. Toxicity was evaluated in mice and SCs. Mechanisms were probed using RT-qPCR, Western blot, co-immunoprecipitation, and ubiquitination assays. LC-MS/MS assessed tissue distribution. Molecular docking and dynamics simulations characterized the Andro-β-TrCP interaction. The results demonstrated that Andro exposure caused significant testicular atrophy, blood-testis barrier (BTB) disruption, and spermatogenic impairment in mice. Meanwhile, pharmacokinetic analysis revealed SCs as the primary target of Andro-induced testicular damage, showing rapid Andro accumulation that was subsequently detected in sperm and the epididymis. Furthermore, Andro triggered ferroptosis in testicular injury and SCs, marked by increased ROS, MDA, iron overload, and lipid peroxidation. These effects were rescued by the ferroptosis inhibitor deferoxamine. Mechanistically, Andro directly bound to β-TrCP, downregulating its expression and subsequently stabilizing ATF4 by impairing its ubiquitin-mediated degradation. Silencing ATF4 inhibited ferroptosis and restored cell viability upon Andro challenge. The direct Andro-β-TrCP interaction was consistently confirmed by molecular docking, dynamics simulations, and CETSA. This study reveals that Andro triggers SCs ferroptosis by inhibiting β-TrCP-mediated ATF4 ubiquitination and degradation, leading to BTB disruption and spermatogenic impairment. These findings provide a theoretical basis for optimizing clinical application of Andro in the future.
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Frontiers in Pharmacology
·
2025
·
IF 4.8
Zhiliang Sun,Zhongshi Zhou,Kezheng Liao,Yanju Liu,Yanyun Liu,Chaoyang Wang,Zhihua Zhang,Li Wen
Background: Non-alcoholic fatty liver disease (NAFLD), a chronic liver disease posing a severe threat to human health, currently lacks specific therapeutic drugs. Our previous studies have demonstrated that Polygala tenuifolia Willd. Extract (EPT) can significantly suppress the PGE2 inflammatory pathway, thereby exerting anti-inflammatory and antioxidant effects, as well as improving lipid metabolism. These findings suggest that EPT might hold potential value for the prevention and treatment of NAFLD.Purpose: This study aims to investigate the role of EPT in NAFLD and its multi - target synergistic mechanisms, and to preliminarily explore its impact on the early progression of NAFLD.Methods: The detection of EPT components in rat blood was performed by UPLC-MS/MS. A rat NAFLD model was established using a high-fat emulsion gavage method, and pathological changes in liver tissue were assessed via H&E, Oil Red O, and Sirius Red staining. RNA-seq, immunohistochemistry, RT-qPCR, and Western blotting were used to evaluate the expression of cyclooxygenase 1 (COX1), cyclooxygenase 2 (COX2), inflammatory factors (IL-1, IL-6, TNF-α), oxidative stress-related proteins in the KEAP1 pathway, proteins involved in the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway, and apoptosis-related proteins (Bcl-2 and Caspase-3).Results: EPT significantly attenuated the histopathological alterations in liver tissue and ameliorated lipid accumulation in the livers of NAFLD rats. RNA-seq identified differential changes in the arachidonic acid metabolism, inflammatory, and endoplasmic reticulum-related pathways. Immunohistochemistry showed that EPT reversed the elevated expression of COX2, the ER stress marker GRP78, and PERK in the liver tissue of model rats. RT-qPCR and Western blot analyses confirmed that EPT reduced the expression of COX1, COX2, IL-1β, IL-6, TNF-α, and KEAP1, while increasing Nrf2 and HO-1 levels. Furthermore, EPT downregulated GRP78, PERK, p-PERK, eIF2α, p-eIF2α, ATF4, CHOP, Bcl-2, and Caspase-3.Conclusion: These results suggest that EPT might exert anti - inflammatory and antioxidant effects by modulating the COX2 pathway in NAFLD rats, downregulate the ER stress PERK - eIF2α - ATF4 signaling pathway, alleviate ER stress, inhibit apoptosis, and delay NAFLD progression.
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