BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
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2023
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IF 5.1
Ziyuan Tong,Yuan Shen,Quan Yuan,Honghao Yu
Despite recent advances in understanding the biological behavior of osteosarcoma (OS), OS is still the most common primary bone sarcoma that endangers the health of children and adolescents. High-temperature requirement A (HTRA) protease family plays an important regulatory role in numerous malignancies and acts as a prognostic biomarker. However, the function and underlying mechanisms of the HTRA family in OS development remain unknown. Through analyzing the GSE126209 dataset obtained from different Gene Expression Omnibus (GEO) databases, we found that HTRA3 as a member of the HTRA family was downregulated in OS tissues compared with that in normal tissues. Functional experiments indicated that HTRA3 overexpression suppressed malignant behaviors of OS cells in vitro and tumor growth in vivo . Mechanistically, we found that HTRA3 co-localized with the X-linked inhibitor of apoptosis protein (XIAP) and decreased XIAP stability. Further investigation showed that XIAP knockdown inhibited the degradation of phosphatase and tensin homolog (PTEN) and that HTRA3 caused the blockage of PTEN/phosphoinositide 3-kinase (PI3K)/AKT pathway, characterized as the reverse of cell function caused by HTRA3 overexpression after PTEN inhibitor BpV (HOpic) treatment. Detailed investigations showed that forkhead box protein 1 (FOXP1), an oncogene in OS progression, downregulated HTRA3 expression and inhibited the transcriptional activity of HTRA3 , suggesting that HTRA3 was regulated negatively by FOXP1. In conclusion, our study demonstrates that HTRA3 is a repressor involved in OS development via the PTEN/PI3K/AKT pathway under the modulation of transcription factor FOXP1, and it may provide a therapeutic direction for OS patients.
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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细胞生物学
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PubMed
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2026
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IF 5.4
Xiaoliang Wang,Mengting Lou,Yuting Wang,Miao-Miao Niu,Dongli Zhang
Lung cancer, a globally prevalent fatal malignancy, remains a major therapeutic challenge. X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in various cancers, driving uncontrolled proliferation, while its specific inhibition suppresses tumour growth. Through virtual screening, we identified five novel candidate peptides (Peptides 1–5) with picomolar-level inhibitory activity. Peptide-5 showed the highest binding affinity (Kd = 10.2 ± 0.5 pM), and FP assay indicated that Peptide-5 competitively binds the BIR3 domain of XIAP against caspase-9. Molecular dynamics simulations confirmed the structural stability of its complex with XIAP. Meanwhile, Peptide-5 showed good serum and metabolic stability, as well as favourable cellular permeability. Notably, Peptide-5 exhibited potent antiproliferative activity against various tumour cells with no obvious toxicity to normal cells. Peptide-5 potentially activates apoptotic signalling through modulating the Bcl-2/Bax mRNA expression. In summary, our study confirms that Peptide-5 is a highly potent and promising XIAP-targeted inhibitor for the treatment of cancer.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Fu-li Shi,Yang-feng Lv,Shi-qi Luo,Yu-xuan Sun,Xiang-qiong Wen,Yue-xiang Ren,Yu-xing Yang,Peng Yu,Qiong-feng Chen,Xian-he Yang,Shan Xu,Jie Qing,Dong-yun Ouyang,Jian-ming Li
Introduction PANoptosis, an inflammatory cell death pathway that integrates pyroptosis, apoptosis, and necroptosis, contributes critically to the pathogenesis of inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). However, the molecular regulation of PANoptosis and its pharmacological intervention remain poorly defined. Objectives This study aimed to investigate the regulatory role of XIAP in PANoptosis and to evaluate the therapeutic potential of luteolin, a natural flavonoid, as a pharmacological inhibitor of PANoptosis. Methods Murine macrophage models were used to assess PANoptosis induction and inhibition. Structural and biochemical approaches were applied to determine the interaction between luteolin and XIAP. Mitochondrial function, ROS accumulation, oxidized mitochondrial DNA, and z-DNA generation were examined, while autophagy was evaluated as a modulatory mechanism. Therapeutic efficacy was further validated in a poly(I:C)/LPS-induced HLH mouse model. Results XIAP was identified as an essential component of the PANoptosome complex, and its knockdown abolished PANoptosis formation. Luteolin directly bound to XIAP, destabilized its structure, and disrupted its interaction with PANoptosome, thereby blocking PANoptosome assembly. Luteolin preserved mitochondrial integrity, reduced ROS accumulation, and inhibited the generation of oxidized mtDNA and z-DNA. Importantly, luteolin enhanced autophagic clearance of damaged mitochondria by relieving XIAP-mediated suppression of autophagy. In vivo, luteolin treatment significantly attenuated systemic inflammation, protected organ function, and improved survival in HLH mice, effects associated with diminished PANoptosome formation and reduced z-DNA accumulation. Conclusions This study establishes XIAP as a central regulator of PANoptosis and demonstrates luteolin as a natural inhibitor targeting XIAP to block PANoptosome assembly and mitochondrial dysfunction. These findings provide a novel pharmacological strategy for treating PANoptosis-driven inflammatory diseases.
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高影响因子
Frontiers in Pharmacology
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2026
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IF 5.4
Xinli Qiu,Lihua Qiang,Yiru Wang,Bingxi Li,Zehui Lei,Jing Wang
Background Staphylococcus aureus (SA) remains a global health threat due to its increasing drug resistance and intracellular persistence, which compromise the conventional antibiotic efficacy. Host-directed therapy (HDT) has emerged as a promising alternative by modulating host immunity. With multi-targeting and immunomodulatory properties, traditional Chinese medicine (TCM) monomers represent ideal candidates for HDT. However, their ability to promote host immunity-mediated SA clearance remains largely unexplored. Methods Forty-one TCM monomers potentially regulating host apoptosis, a core mechanism of the host innate immune defense against intracellular pathogens, were screened to identify a compound that promotes the clearance of intracellular SA and methicillin-resistant SA (MRSA). The mechanism was investigated in infected macrophages using transcriptomics, proteomics, molecular dynamics simulations, and biochemical assays. The physiological function of the TCM monomer was examined in infected mice through lung pathology and multi-omics analysis, including transcriptomics, proteomics, metagenomics, and metabolomics. Results Triptolide was identified as a potent facilitator of host immunity-mediated intracellular clearance of SA and MRSA, without exerting direct bactericidal effects. Mechanistically, triptolide directly binds to the X-linked inhibitor of apoptosis protein (XIAP), disrupting its interaction with caspases to relieve their inhibition and thereby induce apoptosis. Furthermore, in murine infection models, triptolide treatment reduced bacterial loads, alleviated inflammation, and induced macrophage apoptosis in lungs, concurrently maintaining microbiota homeostasis and improving metabolic function. Conclusion This study establishes a proof of concept for triptolide as a HDT candidate against SA and MRSA infections, which not only enhances host apoptosis-mediated pathogen clearance but also maintains host microbiota and metabolic homeostasis.
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高影响因子
Aging-US
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2019
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IF 5.515
Shi Zilu,Huang Qian,Wu Haibin,Ge Chenxu,Lou Deshuai,Li Qiang,Hu Linfeng,Tan Jun,Xu Minxuan
Increasing evidence indicates that prolonged fat-rich diet (HFD) ingestion is a predisposing factor for metabolic disorder-associated system inflammation and oxidative stress injury, which contributes to the occurrence of non-alcoholic fatty liver disease (NAFLD). NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-mediated inflammatory infiltration was determined to participate in NAFLD. X-linked inhibitor of apoptosis protein (XIAP) was recently confirmed as an essential regulator for apoptosis in cells. However, the role of XIAP in HFD-induced NAFLD is still not understood. Here, XIAP was characterized with respect to HFD-induced NLRP3 inflammasome activation and reactive oxygen species (ROS) generation in vivo and palmitate (PA)-treated cells in vitro . After HFD administration, hepatic injury was confirmed via histological assessment (grading and staging of NAFLD) and biochemical parameters, oxidative stress, and reduced antioxidant activity. Up-regulated hepatic dysfunction were further indicated by elevated dyslipidemia, lipid accumulation, and decreased fatty acid β-oxidation associated gene expression. Moreover, in the absence of XIAP, NLRP3 signaling activated by HFD-triggered oxidative stress was up-regulated, accompanied by reduction in antioxidants including HO-1, NQO-1, GST, SOD and Nrf2 activity. The detrimental effects of XIAP blocking on hepatic steatosis and related pathologies were also confirmed in PA-treated mouse liver cells. In contrast, overexpression of XIAP by transfection in vitro restrained PA-stimulated hepatic steatosis by suppression of oxidative stress, NLRP3 related inflammatory response, and impairment of Nrf2 activity, further alleviating abnormal metabolic disorder associated NAFLD. Taken together, the present study helped to elucidate how HFD-induced hepatic steatosis was regulated by XIAP, possibly via the inhibition of NLRP3 signaling and oxidative stress injury.
研究领域:
肝病学
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分子生物学
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免疫学
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代谢紊乱
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高影响因子
CELL BIOCHEMISTRY AND BIOPHYSICS
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2014
·Vol. 71
·期 1
·367-373
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IF 2.38
Gan Maozhou,Yin Xiaodong
This research designed to explore the antitumor activity of puerarin against human mantle cell lymphoma (MCL). Cell proliferation and apoptosis were assessed by MTS and flow cytometry. Caspase-3, -8, and -9 activities were assessed with the colorimetric caspase protease assay. Apoptotic proteins like PARP, cyclin D1, Bcl-2 family, XIAP, and cIAP I were researched by western blot. The PI3K inhibitor LY294002 was used to investigate the possible mechanism relating the PI3K/Akt signaling pathway. Puerarin in vitro inhibited proliferation and induced apoptosis of Z138 cells. Expressions of PI3K and p-Akt were downregulated by puerarin. Puerarin negatively regulated NF-κB activity by inhibiting NF-κB phosphorylation with nuclear translocation inhibition. This kind of effects was correlated with the suppression of expression of cyclin D1, BAX, Bcl-2, XIAP etc. This function was modulated by the PI3K inhibitor. Our results demonstrated that puerarin can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the NF-κB signaling pathway. Puerarin may have therapeutic applications in the treatment of MCL.
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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信号转导
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PubMed
高影响因子
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