Cell Death & Disease
·
2024
·Vol. 15
·期 1
·1-15
·
IF 8.1
Li Jingzhi,Guo Ming,Chen Lin,Chen Zhuchu,Fu Ying,Chen Yongheng
Nasopharyngeal carcinoma (NPC) is a malignant tumor that is highly prevalent in Southeast Asia, especially in South China. The pathogenesis of NPC is complex, and genetic alterations of tumor suppressors and proto-oncogenes play important roles in NPC carcinogenesis. p53 is unexpectedly highly expressed in NPC and possesses an uncommon mutation of R280T, which is different from a high frequency of hotspot mutations or low expression in other tumors. However, the mechanism of p53 loss of function and its correlation with R280T in NPC are still unclear. In this study, p53 amyloid aggregates were found to be widespread in NPC and can be mainly induced by the R280T mutation. Aggregated p53-R280T impeded its entry into the nucleus and was unable to initiate the transcription of downstream target genes, resulting in decreased NPC cell cycle arrest and apoptosis. In addition, NPC cells with p53-R280T amyloid aggregates also contributed aggressively to tumor growth in vivo. Transcriptome analysis suggested that p53 amyloid aggregation dysregulated major signaling pathways associated with the cell cycle, proliferation, apoptosis, and unfolded protein response (UPR). Further studies revealed that Hsp90, as a key molecular chaperone in p53 folding, was upregulated in NPC cells with p53-R280T aggregation, and the upregulated Hsp90 facilitated p53 aggregation in turn, forming positive feedback. Therefore, Hsp90 inhibitors could dissociate p53-R280T aggregation and restore the suppressor function of p53 in vitro and in vivo. In conclusion, our study demonstrated that p53-R280T may misfold to form aggregates with the help of Hsp90, resulting in the inability of sequestered p53 to initiate the transcription of downstream target genes. These results revealed a new mechanism for the loss of p53 function in NPC and provided novel mechanistic insight into NPC pathogenesis.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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遗传学
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高影响因子
MOLECULAR REPRODUCTION AND DEVELOPMENT
·
2026
·Vol. 93
·期 7
·e70135
·
IF 2.6
Yang Sun,Haipeng Pei,Xing Zhang,Yi Jing,Ziheng Zhang,Xinghao Zhang,Huaying Qian,Fengjuan Chang,Yuhang Geng,Ziyang Han,Yun Chen
Pyroptosis, a proinflammatory form of programmed cell death mediated by the NLRP3 inflammasome, has recently been implicated in Sertoli cell inflammatory injury. Crocin, a water-soluble carotenoid glycoside derived from Crocus sativus L. and Gardenia jasminoides Ellis, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties, yet its role in Sertoli cell pyroptosis remains unclear. Here, we investigated the pharmacological effects and mechanisms of crocin in regulating TM4 Sertoli cell viability and pyroptosis. Network pharmacology based on oligoasthenospermia (OA)-related candidate targets, together with molecular docking, identified HSP90AA1 as a candidate molecular target associated with crocin-mediated regulation of Sertoli cell pyroptosis. MST analysis further provided target-engagement evidence supporting a direct interaction between crocin and HSP90AA1. In TM4 Sertoli cells, crocin improved cell viability, enhanced Ki-67 expression, and protected against lipopolysaccharide/nigericin-induced pyroptosis, as evidenced by reduced lactate dehydrogenase release, decreased PI-positive cells, and downregulated expression of IL-1β, IL-18, NLRP3, Caspase-1, and GSDMD. Moreover, under HSP90AA1-overexpressing conditions, crocin partially reduced pyroptosis-related injury and inflammatory mediator expression, supporting the involvement of HSP90AA1 in crocin-mediated regulation of Sertoli cell pyroptosis. Collectively, these findings indicate that crocin enhances Sertoli cell proliferation and mitigates inflammasome-driven pyroptosis through an HSP90AA1-associated mechanism. These findings should be interpreted as preliminary in vitro evidence for crocin-mediated regulation of Sertoli cell proliferation and pyroptosis, and further validation in animal models and clinical samples is required.
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高影响因子
REPRODUCTION
·
2026
·Vol. 171
·期 2
·
IF 3.7
Lin Jiayu,Zhao Weie,Li Manchao,Liu Mingxin,Guo Qi,Wu Taibao,Xiang Yuting,Liu Jiawen,Zeng Yanyan,Liang Qiqi,Liang Xiaoyan,Zhou Chuanchuan,Li Jingjie
Endometriosis, a chronic inflammatory condition characterized by pain and infertility, remains a clinical challenge. Current hormonal and surgical treatments are often limited by side effects and high recurrence rates. In search of more effective and less invasive alternatives, we analyzed a single-cell RNA sequencing dataset of menstrual effluents from patients (GSE203191) and identified a significant upregulation of heat shock protein 90 (HSP90), suggesting its pathogenic involvement. Using primary endometrial stromal cells (ESCs) isolated from human ovarian endometrioma and a murine endometriosis model, we evaluated the therapeutic potential of HSP90 inhibition with 17-allylamino-17-demethoxygeldanamycin (17-AAG). In vitro, 17-AAG (10 nM–10 μM) reduced ESC viability and proliferation in a dose-dependent manner while increasing caspase-3 activity. In vivo, 17-AAG (30 μg/g) significantly attenuated ectopic lesion growth without impairing systemic parameters such as body weight, anti-Müllerian hormone, or estrogen levels. Proteomic profiling revealed disruption of HSP90 client networks, including downregulation of importin 4 and tubulin gamma complex protein 3, and upregulation of DnaJ heat shock protein family member B1, glutamate-ammonia ligase, and sequestosome 1. These findings highlight HSP90 as a promising non-hormonal therapeutic target in endometriosis, offering mechanistic insights and translational potential for more targeted, well-tolerated treatment strategies.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2026
·
IF 5.9
Ke Wang,Tao Xu,Ruixiao Li,Chao Tao,Weiyi Chen,Shiying Mao,Meiling Zhou,Bin Liao,Jinlu Shang,Li Deng
Thermosensitive MGA@Gel enables prolonged intratumoral retention and controlled release. • GA-mediated HSP90 inhibition reduces thermotolerance and enhances PTT efficacy. • MGA@Gel exhibits stable photothermal performance with rapid heating. • MGA@Gel achieves effective tumor inhibition with good biocompatibility in 4T1 mice. Triple-negative breast cancer (TNBC) is highly aggressive and prone to recurrence, and durable therapeutic efficacy is often difficult to achieve with monotherapy. Photothermal therapy (PTT) offers advantages such as minimal invasiveness and spatiotemporal controllability and induces tumor cell death through localized hyperthermia. However, thermal stimulation simultaneously activates protective heat-stress responses in tumor cells, among which the inducible upregulation of heat shock protein 90 (HSP90) enhances thermotolerance and consequently compromises the efficacy of PTT. To overcome this limitation, we proposed a synergistic strategy based on HSP90 inhibition to induce tumor cell apoptosis while sensitizing tumors to PTT, and constructed an intratumorally injectable thermosensitive hydrogel for localized drug delivery. The HSP90 inhibitor geldanamycin (GA) was loaded into mesoporous polydopamine (MPDA) to form MGA, which was subsequently encapsulated within a PNIPAM/β-glucan composite thermosensitive hydrogel, yielding MGA@Gel. Both in vitro and in vivo studies demonstrated that MGA@Gel markedly enhanced antitumor efficacy under near-infrared (NIR) laser irradiation and effectively suppressed HSP90-associated heat-stress tolerance. Notably, in a 4T1 tumor-bearing mouse model, a single intratumoral injection established a sustained local drug depot. When combined with NIR laser irradiation, this system enabled efficient tumor suppression, pronounced downregulation of HSP90 signaling, increased apoptosis, and reduced tumor cell proliferation. These findings confirm that GA, by blocking the heat-stress protective pathway, effectively potentiates the antitumor effects of PTT. Overall, we developed a thermosensitive in situ hydrogel delivery system that enhances PTT via HSP90 inhibition, thereby overcoming tumor thermoresistance and providing a promising strategy for precise local treatment of TNBC.
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高影响因子
Nano Today
·
2022
·
IF 18.962
Chang Liu,Shuolin Li,Ruihao Ma,Chendong Ji,Klaus Müllen,Meizhen Yin
Mild phototherapy with heat shock protein 90 (HSP90) inhibitors can be employed for tumor therapy, but suffers from non-exhaustive therapeutic effects and uncontrollable release. Herein, we present NIR-responsive and dual sensitized nanoparticles for mild tumor phototherapy. These nanoparticles were based on two perylene monoimide and a diamino anthraquinone (2PMI-AQ) chromophore as an inner hydrophobic core. To explore the sensitized function, 2PMI-AQ was modified with hydrophilic thermosensitive polymers, resulting in stable nanoparticles (NP1) via spontaneous self-assembly. The as-prepared NP1 possess a robust nanostructure and enable combined photothermal therapy (PTT) and photodynamic therapy (PDT). Besides, outside thermosensitive polymers of NP1 allow loading and photothermal release of HSP90 inhibitors. Under NIR laser irradiation, photothermal/photodynamic effects and photothermally controlled release of HSP90 inhibitors are realized simultaneously. The inhibitors inactivate the cell guardian protein HSP90 to attenuate the cytoprotection , which enhances both PTT and PDT. We thus achieve mild tumor phototherapy in vivo by using NIR-absorbing nanoparticles with dual sensitized function induced by low-power irradiation.
研究领域:
肿瘤学
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纳米医学
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生物材料学
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高影响因子
OncoTargets and Therapy
·
2022
·
IF 4.345
Xiaoli Li,Guangbei Zhu,Xintong Yao,Ning Wang,Ronghui Hu,Qingxin Kong,Duanfang Zhou,Liangyuan Long,Jiali Cai,Weiying Zhou
Background Celastrol is a major active component of the thunder god vine (Tripterygium wilfordii) used in traditional Chinese medicine to treat chronic inflammatory and autoimmune diseases. Celastrol inhibits PI3K–Akt–mTOR signaling, which is frequently dysregulated in tumors and critical for tumor-cell proliferation and survival, but the underlying mechanisms are still not fully understood. In the present study, we investigated detailed mechanisms of celastrol inhibition of mTOR signaling in breast cancer cells.Methods First, we evaluated the effect of celastrol on breast cancer-cell growth using MTT assays. Second, we examined the effects of celastrol on mTOR phosphorylation and expression using Western blot. Furthermore, we investigated the cause of mTOR downregulation by celastrol using immunoprecipitation assays. In addition, we evaluated the effect of celastrol on an MDA-MB231 cell-derived xenograft model.Results Celastrol suppressed breast cancer cell growth in vitro and in vivo. Celastrol inhibited mTOR phosphorylation and induced mTOR ubiquitination, resulting in its proteasomal degradation. Mechanistically, we found that mTOR is a client of Hsp90–Cdc37 chaperone complex, and celastrol disrupts mTOR interaction with chaperone Hsp90 while promoting mTOR association with cochaperone Cdc37.Conclusion Our study reveals that celastrol suppresses mTOR signaling, at least in part through regulating its association with chaperones and inducing its ubiquitination.
研究领域:
肿瘤学
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药理学
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分子生物学
·
传统中药
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Antioxidants
·
2025
·Vol. 14
·期 8
·914
·
IF 6.6
Pengxin Jiang,Kangping Liu,Yanan Cui,Puyu Liu,Xutao Wang,Zijuan Hou,Jiamei Cui,Ning Chen,Jinghui Fan,Jianguo Li,Yuzhu Zuo,Yan Li
EnterotoxigenicEscherichia coli(ETEC) leads to severe diarrhea in piglets. Naringenin (Nar), a natural flavonoid compound, is known for its antibacterial and anti-antioxidant properties. However, the protective effects of Nar against ETEC-induced diarrhea have not been reported yet. This study investigated the protective mechanisms of Nar against ETEC infection in porcine intestinal epithelial cells (IPEC-J2). ETEC infection induced oxidative stress and ferroptosis in IPEC-J2 cells by elevating intracellular iron content and ROS accumulation, increasing MDA levels, downregulating SOD activity and GPX4 expression, and upregulating the transcription of CHAC1 and SLC7A11. In contrast, Nar suppressed ETEC-induced ferroptosis of IPEC-J2 cells by inhibiting the SLC7A11/GPX4 pathway. Specifically, Nar mitigated mitochondrial damage, reduced intracellular iron levels and ROS accumulation, and ultimately reversed the oxidative stress. Network pharmacology and molecular docking identified heat-shock protein 90 (HSP90) as a potential target of Nar. Overexpression and knockdown experiments revealed that ETEC-induced ferroptosis was mediated by upregulation of HSP90, while the protective effects of Nar against ETEC-induced ferroptosis were dependent on the downregulation of HSP90. In conclusion, Nar targets host HSP90 to protect IPEC-J2 cells from ferroptosis caused by ETEC infection. This study demonstrates that Nar is a potent antioxidant natural compound with potential for preventing ETEC-induced intestinal damage.
研究领域:
兽医学
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微生物学
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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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天然产物化学
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JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Yuanzheng Huang,Chongqin Pan,Baoping Lian,Jiaqian Du,Minxin Cao,Liu Yang,Dandan Zhu,Wen Gao,Lei Wang,Shentong Fang,Xiaoxuan Liu
Abstract Conventional single-target drugs frequently suffer from limited efficacy and drug resistance. Here, we report an amphiphilic peptide dendrimer that integrates intrinsic bioactivity and nanocarrier functions, establishing a novel “drug-bioactive carrier” paradigm for multi-target cancer therapy. Using reverse molecular docking and limited proteolysis-mass spectrometry (LiP-MS), heat shock protein 90 (HSP90) was identified as a prominent candidate intracellular target of the dendrimer. Structure-activity relationship studies revealed that amphiphilic balance and dendrimer topology govern self-assembly and HSP90 modulation, with C16-KK2 displaying optimal activity by disrupting HSP90-CDC37 interaction and promoting degradation of oncogenic client proteins. Importantly, C16-KK2 nanoassemblies effectively encapsulate hydrophobic anticancer drugs, enhancing intracellular delivery and yielding synergistic therapeutic effects with rapamycin and sorafenib. In vivo, sorafenib-loaded C16-KK2 nanoparticles exhibited superior tumor accumulation and enhanced antitumor efficacy compared to free drug treatment. This work presents a mechanistically defined and structurally feasible bioactive nanocarrier platform, advancing rational design strategies for multi-target cancer therapeutics.
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Journal of Advanced Research
·
2026
·
IF 17.1
Qianyu Zhang,Ying Zhang,Chen Wang,Lirun Zhou,Tong Yang,Qianru Zhu,Zheng Chu,Junzhe Zhang,Mengyao Jiang,Jigang Wang,Huanhuan Pang,Chengchao Xu,Huan Tang
Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by chronic inflammation and fibroblast activation, with limited treatment options. The bioactive diterpenoid andrographolide (AP) exhibits anti-inflammatory and antifibrotic properties, but its direct molecular targets and precise mechanism remain unclear. Objectives This study aimed to identify the primary functional target of AP and elucidate the molecular mechanism underlying its therapeutic effects against pulmonary fibrosis. Methods We employed activity-based protein profiling (ABPP) to identify covalent targets of AP in macrophages. Functional validation was performed using siRNA knockdown, enzymatic assays, molecular docking, and biophysical analyses. The therapeutic efficacy and target dependency of AP were evaluated in bleomycin-induced pulmonary fibrosis and LPS-induced acute lung injury mouse models, utilizing lung-specific Ptges3 knockdown. Results AP covalently bound to Cys58 of prostaglandin E synthase 3 (Ptges3), an allosteric site distinct from its catalytic and Hsp90-binding regions. This binding inhibited Ptges3 enzymatic activity, reduced prostaglandin E2 (PGE 2 ) production, and disrupted the Ptges3-Hsp90 chaperone complex, leading to suppressed NF-κB signaling. Genetic knockdown of Ptges3 significantly attenuated the anti-inflammatory and antifibrotic effects of AP both in vitro and in vivo . Conclusions Our findings establish Ptges3 as a critical functional target of AP. AP attenuates pulmonary fibrosis through a dual mechanism involving covalent inhibition of Ptges3 and disruption of the Ptges3-Hsp90-NF-κB axis, highlighting AP as a promising therapeutic agent and Ptges3 as a novel druggable target for IPF.
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高影响因子
Scientific Reports
·
2024
·Vol. 14
·期 1
·1-15
·
IF 3.8
Chen Linli,Guo Xiaojing,Lin Wen,Huang Yingying,Zhuang Suling,Li Qianfeng,Xu Jianhua,Ye Shengnan
Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies.
研究领域:
肿瘤学
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病毒学
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分子生物学
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药理学
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高影响因子
BMC Pharmacology & Toxicology
·
2025
·Vol. 26
·期 1
·1-13
·
IF 2.7
Fu Wenying,Lu Hui,Yan Ying,Shu Chongchong,Xu Chenxin,Chen Yinghua,Xia Yiqun,Chen Jundixia,Chen Yunzhi,Zou Peng,Cui Ri,Ni Daoyong
Section
Background
Lung cancer continues to rank as a leading cause of cancer-related mortality worldwide. Despite notable advances in medical research, therapeutic options for advanced-stage lung cancer remain inadequate. Heat shock protein 90 (HSP90) has been identified as a potential therapeutic target in multiple malignancies, such as lung and colon cancers, owing to its pivotal role in stabilizing numerous oncoproteins. Nonetheless, the clinical application of HSP90 inhibitors has faced challenges, including suboptimal efficacy and the development of resistance mechanisms. B-AP15 is a promising small molecule in cancer therapy that functions by inhibiting deubiquitinating enzymes, which regulate protein degradation through the proteasome pathway. In this study, we aim to investigate its combinatorial activity with the HSP90 inhibitor tanespimycin (TAU) in lung cancer cells.
Section
Methods
The levels of the specified molecules were measured by Western blot analysis. Reactive oxygen species (ROS) levels were determined using the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. 53BP1 foci formation and C/EBP homologous protein (CHOP) expression were assessed by immunofluorescence. Autophagic flux was monitored using mRFP-GFP-tagged microtubule-associated protein 1 light chain 3 (LC3) lentivirus.
Section
Results
Our findings reveal that the combination of TAU and B-AP15 induces significant synergistic antitumor effects, characterized by substantial accumulation of ROS. This ROS accumulation serves as a crucial mediator of the enhanced therapeutic response elicited by the combination treatment. Mechanistic analyses further demonstrated that the combined treatment induces cell death via activation of endoplasmic reticulum (ER) stress and the c-Jun N-terminal kinase (JNK) pathway.
Section
Conclusion
In summary, our study provides robust evidence supporting the potential of combining TAU with B-AP15 as a viable therapeutic option for lung cancer treatment.
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Food Bioscience
·
2023
·
IF 5.2
Yanping Fan,Meilan Xue,Tianhu Shan,Yixian Bai,Huaqi Zhang,Man Liu,Peng Wang,Xi Liang,Hui Liang
Alcoholic liver fibrosis (ALF) is a reversible pathological change in the liver caused by chronic alcohol consumption and is associated with the activation of hepatic stellate cells . Recent findings suggest that niacin can lower triglyceride levels and exert potent antioxidant effects in liver damage. However, the therapeutic effects and molecular mechanisms of niacin in liver fibrosis remain unclear. Therefore, this study aimed to investigate the effects and mechanisms of niacin in ALF using in vivo and in vitro experiments. To establish a murine model of ALF, male C57BL/6N mice were fed a Lieber–DeCarli liquid diet containing 4 % (vol/vol) ethanol and injected with carbon tetrachloride twice weekly (2 mL/kg) for 8 weeks. L-02 and LX2 cells were treated with 400 μM acetaldehyde for 24 h to establish an in vitro ALF model. Serum parameters were examined to investigate the protective effects of niacin against ALF, and network pharmacology was used to identify potential targets and pathways of niacin. Niacin protects against ALF by suppressing the serum levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase , and alkaline phosphatase . Additionally, niacin treatment ameliorated liver fibrosis by improving the antioxidant system, inhibiting heat shock protein 90 (HSP90) activation, promoting signal transducer and activator of transcription 3 (STAT3) ubiquitination , and suppressing the JAK1/STAT3 signaling pathway . Collectively, this study provides experimental evidence that niacin protects against ALF by downregulating the HSP90/JAK1/STAT3 signaling pathway.
研究领域:
药理学
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肝病学
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分子生物学
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细胞生物学
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