International Journal of Biological Sciences最新文献

{"title":"<i>Solobacterium moorei</i> promotes tumor progression via the Integrin α2/β1-PI3K-AKT-mTOR-C-myc signaling pathway in colorectal cancer.","authors":"Yan Chen, Ying Qin, Tingting Fan, Cheng Qiu, Yijie Zhang, Mengmeng Dai, Yaoyao Zhou, Qinsheng Sun, Yuan Guo, Yue Hao, Yuyang Jiang","doi":"10.7150/ijbs.102742","DOIUrl":"10.7150/ijbs.102742","url":null,"abstract":"<p><p>More and more evidences show that the imbalance of intestinal flora homeostasis can contribute to the progression of colorectal cancer (CRC). <i>Solobacterium moorei (S. moorei)</i>, an anaerobic Gram-positive bacillus, was found to be enriched in fecal samples from CRC patients. However, the signaling regulatory mechanism of <i>S. moorei</i> promoting CRC progression remain unknown. Three CRC mouse models (<i>Apc^Min/+</i> mice, AOM/DSS-treated mice and subcutaneous colorectal xenograft mice) and two cell lines (DLD-1 and HT-29) were used to investigate the biological functions and molecular mechanisms of <i>S. moorei</i> on tumor progression of CRC <i>in vivo</i> and <i>in vitro</i>. <i>S. moorei</i> abundance increased in fecal samples and tumor tissues, and was significantly positively correlated with tumor staging of CRC. <i>S. moorei</i> promoted tumor progression in various CRC mouse models and it selectively adhered to cancer cells in comparison to colonic mucosal epithelial cells, enhancing CRC cell proliferation and inhibiting cell apoptosis. Mechanistically, <i>S. moorei</i> cellwall protein Cna B-type domain-containing protein binds to integrin α2/β1 on CRC cells, leading to the activation of PI3K-AKT-mTOR-C-myc pathway via phospho-FAK, thereby promoted tumor cell growth and progression. Blockade of integrin α2/β1 abolished <i>S. moorei</i>-mediated oncogenic response <i>in vitro</i> and <i>in vivo</i>. In summary, this study demonstrated that <i>S. moorei</i> promoted tumor progression via the integrin α2/β1-PI3K-AKT-mTOR-C-myc signaling pathway, which is a novel specific pathogen-mediated mechanism that might be a new potential target for CRC prevention, diagnosis, and treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 4","pages":"1497-1512"},"PeriodicalIF":8.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prp19/CDC5L promotes gastric cancer via activation of the MAPK pathway-mediated homologous recombination.","authors":"Shengkui Qiu, Feiran Wang, Xuesong Gao, Weiyu Guan, Ting Dai, Lei Yin, Fei Wang, Jinjie Sun, Peng Guo, Hao Wu, Shichun Feng, Chong Tang","doi":"10.7150/ijbs.101962","DOIUrl":"10.7150/ijbs.101962","url":null,"abstract":"<p><p><b>Background:</b> Recent advances in gastric cancer (GC) treatment have not substantially improved the 5-year survival rate nor have they significantly reduced the high recurrence rate. This highlights the need for further research to explore the underlying mechanisms of GC. Cell Division Cycle 5-Like Protein (CDC5L) has been implicated in various malignant behaviors of tumors. <b>Methods:</b> We investigated the expression of CDC5L in gastric cancer (GC) using data from The Cancer Genome Atlas (TCGA) and clinical specimens. To explore the role of CDC5L in GC, we conducted <i>in vitro</i> and <i>in vivo</i> assays, alongside molecular mechanism studies using luciferase reporter assays, co-immunoprecipitation (CO-IP), and mass spectrometry (MS). <b>Results:</b> Our findings indicate a significant elevation of CDC5L in GC, with CDC5L overexpression correlating with poorer survival outcomes, advanced TNM stages, and higher pathological grades in GC patients. <i>In vitro</i>, interference of CDC5L markedly inhibited GC progression. We discovered that the Pre-mRNA Processing Factor 19 (Prp19) directly binds to the CDC5L promoter, enhancing its transcription and inhibiting its lysosome-mediated degradation. Additionally, CO-IP and MS assays revealed that CDC5L interacts with MAPK1, activating the MAPK signaling axis and consequently augmenting homologous recombination in GC. <b>Conclusions:</b> In summary, our study confirms that Prp19 upregulates CDC5L expression, which binds to MAPK1, thereby promoting GC progression via the MAPK pathway-mediated homologous recombination. Targeting CDC5L could be a promising strategy in the precision therapy of GC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 4","pages":"1603-1618"},"PeriodicalIF":8.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SEC61G Facilitates Brain Metastases via Antagonizing PGAM1 Ubiquitination and Immune Microenvironment Remodeling in Non-Small Cell Lung Cancer.","authors":"Changshuai Zhou, Yuechao Yang, Huanhuan Cui, Sen Li, Zhisu Wang, Lei Chen, Mingtao Feng, Deheng Li, Xin Chen, Bin Hao, Xiaojun Wu, Yang Gao, Liangdong Li, Jiayan Chen, Yiqun Cao","doi":"10.7150/ijbs.109187","DOIUrl":"10.7150/ijbs.109187","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Brain metastases are a leading cause of mortality in non-small cell lung cancer (NSCLC), yet their molecular mechanisms remain unclear. SEC61G, a subunit of the SEC61 translocon, has been implicated in tumor progression but its role in brain metastases is unknown. This study explores how SEC61G contributes to brain metastases by driving metabolic reprogramming and immune microenvironment remodeling. &lt;b&gt;Methods:&lt;/b&gt; Brain-metastatic NSCLC cell lines were established through &lt;i&gt;in vivo&lt;/i&gt; selection in a mouse model. SEC61G expression was analyzed via transcriptomics, immunohistochemistry, multiplex immunofluorescence, and patient datasets. Functional assays were used to assess SEC61G's role in glycolysis, TLS formation, and immune interactions, with a focus on the SEC61G-PGAM1 axis. Pharmacological inhibitors and co-culture systems were employed to validate findings. &lt;b&gt;Results:&lt;/b&gt; SEC61G was identified as a key upregulated gene in brain metastases based on transcriptomic data from patient-derived samples and mouse models. Higher SEC61G expression in brain metastases correlated with advanced tumor stages and poor survival in NSCLC patients. Mechanistically, SEC61G promoted brain metastasis by stabilizing the key glycolytic enzyme PGAM1. This occurred through a novel mechanism of competitive inhibition of PGAM1 ubiquitination: SEC61G directly antagonized the E3 ubiquitin ligase UBE3C, preventing PGAM1 degradation via the proteasome pathway. Stabilized PGAM1 enhanced glycolysis and regulated oxidative phosphorylation, driving metabolic reprogramming that supported brain metastatic colonization. Moreover, SEC61G reshaped the tumor immune microenvironment by promoting microglial M2 polarization and suppressing M1 polarization, accompanied by increased secretion of IL-6 and IL-10. These immune effects were dependent on PGAM1, as its pharmacological inhibition reversed SEC61G-induced M2 polarization and restored CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration. &lt;i&gt;In vivo&lt;/i&gt; and clinical studies confirmed that high SEC61G expression in brain metastases correlated with excessive M2 microglia, reduced immune surveillance, and poor patient outcomes. Immunoprofiling revealed a striking gradient of SEC61G expression across tertiary lymphoid structures (TLS) maturation stages: SEC61G levels were highest in TLS-absent samples and CD206&lt;sup&gt;+&lt;/sup&gt; microglia infiltration, intermediate in samples with immature TLS, and lowest in those with mature TLS. &lt;b&gt;Conclusion:&lt;/b&gt; In conclusion, this study identifies a novel mechanism in which SEC61G drives NSCLC brain metastases by competitively inhibiting UBE3C-mediated ubiquitination of PGAM1, stabilizing PGAM1 and enhancing glycolysis. In addition to metabolic reprogramming, SEC61G impairs TLS maturation, suppresses adaptive immune responses, and facilitates immune evasion, contributing to brain metastatic colonization. These findings highlight SEC61G as a key regulator of brain metastasis and a promising","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 4","pages":"1436-1458"},"PeriodicalIF":8.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>FTO</i>-induced <i>APOE</i> promotes the malignant progression of pancreatic neuroendocrine neoplasms through <i>FASN</i>-mediated lipid metabolism.","authors":"Jinhao Chen, Mujie Ye, Danyang Gu, Ping Yu, Lin Xu, Bingyang Xue, Lijun Yan, Feiyu Lu, Chunhua Hu, Yanling Xu, Xiaoting Shi, Lingyi Chen, Yan Wang, Jianan Bai, Ye Tian, Qiyun Tang","doi":"10.7150/ijbs.103428","DOIUrl":"10.7150/ijbs.103428","url":null,"abstract":"<p><p>N6-methyladenosine (m6A) is considered the most prevalent RNA epigenetic regulator in cancer. FTO, an m6A demethylase, has been implicated in contributing to the progression of various cancers by up-regulating the expression of multiple oncogenes. However, studies exploring its impact on lipid metabolism in cancer, especially in pNENs, remain scarce. In this study, we demonstrated that FTO was up-regulated in pNENs and played a critical role in tumor growth and lipid metabolism. Mechanistically, we discovered that FTO over-expression increased the expression of APOE in an m6A-IGF2BP2-dependent manner, leading to dysregulation of lipid metabolism. Furthermore, we found APOE could activate the PI3K/AKT/mTOR signaling pathway, thereby enhancing lipid metabolism and proliferative capabilities, by orchestrating the state of FASN ubiquitination. In conclusion, our study reveals the FTO/IGF2BP2/APOE/FASN/mTOR axis as a mechanism underlying aberrant m6A modification in lipid metabolism and provides new insights into the molecular basis for developing therapeutic strategies for pNENs treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 4","pages":"1478-1496"},"PeriodicalIF":8.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N⁶-methyladenosine Reader IGF2BP2-modified HMMR Promotes Non-small Cell Lung Cancer Metastasis via Interaction with MAP4K4.","authors":"Jiansheng Zhang, Mengzhu Zhang, Aimin Qiu, Chang Li, Qiongju Chen, Jianjun Li, Yuanyuan Zeng, Jianjie Zhu, Jian-An Huang, Xiuqin Zhang, Zeyi Liu","doi":"10.7150/ijbs.104097","DOIUrl":"10.7150/ijbs.104097","url":null,"abstract":"<p><p>Globally, lung cancer represents the leading cause of cancer-related mortality, with 85% of cases attributable to non-small cell lung cancer (NSCLC). Metastatic progression remains a major challenge in treating advanced lung cancer, resulting in a dismal five-year survival rate of 20-30%. Hyaluronan mediated motility receptor (HMMR) has been identified as a novel oncogene in NSCLC. However, its exact role and mechanisms in NSCLC and metastasis are yet to be fully understood. Elevated mRNA and protein levels of HMMR were observed in human NSCLC tumors in comparison with normal adjacent tissues. Increased HMMR expression was associated with poorer prognosis, with multivariate Cox regression analysis also identifying it as an independent prognostic factor. HMMR knockdown inhibited tumor cell migration and invasion, while its overexpression enhanced these processes. Mechanistically, HMMR promotes tumor metastasis by binding to mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which activates the p-JNK/p-c-JUN/MMP1 signaling cascade. The effects of HMMR overexpression on metastatic potential and JNK signaling were confirmed by MAP4K4 knockdown or GNE-495 treatment. Additionally, insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) was found to bind to the N⁶-methyladenosine (m⁶A) site of HMMR, increasing mRNA stability and HMMR expression levels. In a mouse model, the MAP4K4 inhibitor GNE-495 successfully suppressed lung metastasis induced by HMMR overexpression. These results offer valuable insights into HMMR's biological functions while suggesting potential avenues for novel treatments.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 4","pages":"1391-1409"},"PeriodicalIF":8.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844294/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ugonin P facilitates chondrogenic properties in chondrocytes by inhibiting miR-3074-5p production: implications for the treatment of arthritic disorders.","authors":"Ting-Kuo Chang, Trung-Loc Ho, Yen-You Lin, Le Huynh Hoai Thuong, Kuan-Ying Lai, Chun-Hao Tsai, Chih-Chuang Liaw, Chih-Hsin Tang","doi":"10.7150/ijbs.108789","DOIUrl":"10.7150/ijbs.108789","url":null,"abstract":"<p><p>Arthritis is a chronic inflammatory disease that causes joint damage, with osteoarthritis (OA) and rheumatoid arthritis (RA) being the most common types. Both conditions are characterized by cartilage degradation due to an imbalance between repair and breakdown processes. Chondrocytes, the key cells in articular cartilage, maintain its structure by producing an extracellular matrix rich in aggrecan and type II collagen (COL2). MicroRNAs (miRNAs), small noncoding RNAs, regulate genes critical for cartilage balance and are involved in the progression and treatment of OA and RA. Recently, herbal medicines have gained attention for arthritis treatment. Ugonin P, a flavonoid from <i>Helminthostachys zeylanica Hook</i>, is known for its antioxidant and anticancer effects, but its role in cartilage homeostasis is unclear. This study explores ugonin P's chondrogenic effects and its molecular mechanisms involving miRNA regulation. Analysis of Gene Expression Omnibus (GEO) data and clinical samples revealed reduced aggrecan and COL2 levels in OA and RA, while miR-3074-5p levels were elevated, suppressing these proteins. Ugonin P, without affecting cell viability, enhanced aggrecan and COL2 production and promoted chondrocyte differentiation by downregulating miR-3074-5p and activating MAPK pathways. These findings suggest ugonin P as a promising therapeutic candidate for arthritis management.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 4","pages":"1378-1390"},"PeriodicalIF":8.2,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11844289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activated AXL Ameliorates Alcohol-associated Steatotic Liver Ischemia-Reperfusion Injury by Inhibiting ER stress and Mitochondria-associated Apoptosis.","authors":"Qi Fang, Qi Yan, Xingyun Liu, Xiaolu Zhang, Lixia Zha, Ruixin Zhang, Zhixin Gao, Jian Du, Lijian Chen","doi":"10.7150/ijbs.103789","DOIUrl":"10.7150/ijbs.103789","url":null,"abstract":"<p><p>Hepatic ischemia-reperfusion (I/R) injury can cause poor prognosis of liver transplantation and hepatectomy, especially in patients with alcohol-associated liver disease (ALD). Apoptosis is closely related to different stages of liver injury, and the death of hepatocytes caused by endoplasmic reticulum (ER) and mitochondria homeostasis perturbation may be key to liver injury. The receptor tyrosine kinases AXL encoded by the gene axl, is a member of the TAM (TYRO3, AXL, and MERTK) family, which participates in various biological processes by binding to the ligand of growth arrest-specific protein 6 (Gas6). However, whether AXL is involved in apoptosis pathways, and the detailed mechanism in hepatic I/R injury remains unknown. In the present study, we found that total AXL is up-regulated while phosphorylated AXL (p-AXL, the active form of AXL) was down-regulated after I/R in human liver tissues from liver transplantation. Consistently, total AXL was found up-regulated while p-AXL was down-regulated during hepatic I/R injury in mice. Pretreatment with Gas6 increased p-AXL expression, reduced ER stress-associated cell apoptosis, alleviated liver damage, and restored ER and mitochondria ultrastructure during hepatic I/R in mice. Furthermore, the ALD model was established by chronic-plus-binge ethanol feeding to explore the role of AXL in I/R liver injury with ethanol-associated steatosis. We found that ALD mice had a lower p-AXL level and were more susceptible to hepatic I/R injury. Importantly, activated AXL ameliorated liver injury by inhibiting IRE1 and PERK pathway to reduce ER stress-associated apoptosis. In conclusion, activated AXL protects alcohol-associated steatotic liver against I/R injury by inhibiting ER stress and mitochondria-associated apoptosis, suggesting that targeting AXL serves as a potential strategy for liver I/R injury, particularly for marginal liver donors with alcohol-associated steatosis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 3","pages":"1294-1307"},"PeriodicalIF":8.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomal <i>miR-375-3p</i> mediated lipid metabolism, ferritinophagy and CoQ-dependent pathway contributes to the ferroptosis of keratinocyte in SJS/TEN.","authors":"Chen Zhang, Pei Qiao, ChunYing Xiao, ZiPeng Cao, JiaoLing Chen, Hui Fang, JianKang Yang, ZeHua Kang, ErLe Dang, Shuai Shao, BingYu Pang, QingYang Li, ZhenLai Zhu, ShengXian Shen, Akito Hasegawa, Riichiro Abe, HongJiang Qiao, Gang Wang, Meng Fu","doi":"10.7150/ijbs.98592","DOIUrl":"10.7150/ijbs.98592","url":null,"abstract":"<p><p>Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) manifest life-threatening cutaneous adverse drug reactions characterized by keratinocyte death. Previous studies have indicated that apoptosis and necroptosis are implicated in SJS/TEN pathogeneses. However, other forms of cell death involved in this process remain unidentified. Ferroptosis, cell death driven by iron-dependent lipid peroxidation, has been implicated in various human diseases. In this study, the identification of ferroptosis and the potential effects of ferroptosis on SJS/TEN were investigated. We demonstrated that the skin lesions and plasma of SJS/TEN patients show increased levels of lipid peroxidation and iron. The biomarkers of ferroptosis correlated positively with the disease severity in SJS/TEN patients. Besides, plasma exosomes derived from patients with SJS/TEN exhibited elevated levels of cellular oxidized polyunsaturated fatty acids (PUFAs) and phospholipids phosphatidylethanolamine (PE), the key phospholipids that drive cells towards ferroptotic death. <i>miR-375-3p</i>, enriched in plasma-derived exosomes from SJS/TEN patients, was observed reduce both ferritin heavy chain 1 (FTH1) and ferroptosis suppressor protein 1 (FSP1) expression. Parallelly, exosomal <i>miR-375-3p</i> overexpression increased the level of lipid peroxidation but decreased the coenzyme Q10 (CoQ10), thus enhancing the ferroptosis rate of keratinocyte. Above all, we concluded that ferritinophagy-mediated ferroptosis, lipid metabolism, and the FSP1-CoQ-dependent pathway in ferroptosis are critical mechanisms contributing to SJS/TEN. Targeting ferroptosis in keratinocyte may be a therapeutic strategy for preventing SJS/TEN in the future.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 3","pages":"1275-1293"},"PeriodicalIF":8.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM32 promotes neuronal ferroptosis by enhancing K63-linked ubiquitination and subsequent p62-selective autophagic degradation of GPX4.","authors":"Xin Zhou, Yuqing Zhao, Shixue Huang, Haoming Shu, Yinuo Zhang, Haiyuan Yang, Yilong Ren, Xuhui Zhou, Wei Liu, Tengfei Song, Jianquan Zhao, Jun Ma","doi":"10.7150/ijbs.106690","DOIUrl":"10.7150/ijbs.106690","url":null,"abstract":"<p><p>Ferroptosis, characterized by iron-dependent phospholipid peroxidation, is recognized as one of the cell death pathways activated following spinal cord injury (SCI). However, the precise regulatory mechanisms governing this process remain poorly understood. Here, this study identified TRIM32, an E3 ubiquitin ligase, as a key enhancer of neuronal ferroptosis. TRIM32 promoted neuronal ferroptosis by accelerating the degradation of GPX4, which is an essential inhibitor of ferroptosis. Conditional deletion of <i>Trim32</i> in neurons markedly inhibited neuronal ferroptosis and promoted neuronal survival, eventually improving mouse locomotor functional recovery after SCI. However, overexpression of <i>Trim32</i> showed aggravated neuronal loss and poor behavioral function, which could be attenuated by ferroptosis inhibitor Liproxstatin-1. Mechanistically, TRIM32 interacted with GPX4, promoted K63-linked ubiquitination modification of GPX4 at K107, thus enhanced p62-dependent autophagic degradation of GPX4. Moreover, ROS-ATM-Chk2 signaling pathway phosphorylates TRIM32 at S55, further contributing to GPX4 ubiquitination and degradation and subsequent neuronal ferroptosis after SCI, suggesting a positive feedback loop between ROS and TRIM32. Clinically, lipid peroxidation was significantly promoted in patients with SCI. These findings reveal that TRIM32 functions as a neuronal ferroptosis enhancer which is detrimental to neuronal survival and locomotor functional recovery in mice after SCI by promoting K63-linked ubiquitination and subsequent p62-dependent autophagic degradation of GPX4, suggesting a promising therapeutic target for SCI.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 3","pages":"1259-1274"},"PeriodicalIF":8.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DDX17-Mediated Upregulation of CXCL8 Promotes Hepatocellular Carcinoma Progression <i>via</i> Co-activating β-catenin/NF-κB Complex.","authors":"Hui Liu, Xiaoliang Gao, Wenyao Zhang, Xin Fu, Jing Zhang, Qiangqiang Yuan, Jing Jin, Xinyu Du, Renlong Li, Yan Li, Jun Yu, Qiujin Zhang, Xianchun Gao, Liang Zhang, Yuwei Ling, Jing Wu, Lin Wang, Jinliang Xing, Fulin Chen, Yongzhan Nie","doi":"10.7150/ijbs.104165","DOIUrl":"10.7150/ijbs.104165","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a well-known inflammation-related cancer, that accounts for fifth most prevalent neoplasm and the third major driver of cancer associated fatality globally. Accumulating evidence has elucidated that C-X-C motif chemokine ligands (CXCLs) are aberrantly upregulated in HCC and are involved in inflammation-induced hepatocarcinogenesis and metastasis. Herein, we identified a novel function of DEAD-box RNA helicase 17 (DDX17) as an oncogenic factor via transactivating CXCL8 in HCC. Unlike the adjacent nontumor tissues, DDX17 was highly expressed in tumor tissues compared in two independent cohorts and that it acts as an independent prognostic indicator for patients who have HCC. Mechanistically, DDX17 interacts with β-catenin and NF-κB, and promotes their nuclear translocation to promote the transcription of the inflammatory gene CXCL8, thus promoting HCC proliferation and invasion <i>in vitro</i> and <i>in vivo</i>. More interestingly, stimulation with recombinant human CXCL8 augmented the interaction of NF-κB with DDX17/β-catenin and enhanced its autocrine activation by promoting the phosphorylation of IκBα. Furthermore, blocking the association of the DDX17/β-catenin/NF-κB complex with a CXCR1/2 inhibitor markedly abrogated DDX17-mediated HCC proliferation and metastasis. Overall, this study provided new insights into DDX17-mediated pro-inflammatory chemokine activation, which unveiled the association between DDX17 and β-catenin/ NF-κB complex in transactivating the expression of CXCL8. The usage of CXCR1/2 inhibitor to block DDX17-induced CXCL8 signaling activation might be a potential therapeutic approach for HCC treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 3","pages":"1342-1360"},"PeriodicalIF":8.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}