Cell Biology and Toxicology最新文献

{"title":"The roles of lactate and the interplay with m⁶A modification in diseases.","authors":"Fajuan Tang, Dongqiong Xiao, Xihong Li, Lina Qiao","doi":"10.1007/s10565-024-09951-9","DOIUrl":"10.1007/s10565-024-09951-9","url":null,"abstract":"<p><p>Lactate exhibits various biological functions, including the mediation of histone and non-histone lactylation to regulate gene transcription, influencing the activity of T lymphocytes, NK cells, and macrophages in immune suppression, activating G protein-coupled receptor 81 for signal transduction, and serving as an energy substrate. The m⁶A modification represents the most prevalent post-transcriptional epigenetic alteration. It is regulated by m⁶A-related regulatory enzymes (including methyltransferases, demethylases, and recognition proteins) that control the transcription, splicing, stability, and translation of downstream target RNAs. Lactate-mediated lactylation at histone H3K18 can modulate downstream target m⁶A modifications by enhancing the transcriptional expression levels of m⁶A-related regulatory enzymes. These enzymes play a crucial role in the progression of diseases such as cancer, fibrosis (in both liver and lung), myocardial ischemia, cerebral hemorrhage, and sepsis. Furthermore, m⁶A-related regulatory enzymes are also subject to lactylation by lactate. In turn, these regulatory enzymes can influence key glycolytic pathway enzymes or modify lactate transporter MCT4 via m⁶A alterations to impact lactate levels and subsequently affect lactylation processes.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"107"},"PeriodicalIF":5.3,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11609124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human liver progenitor-like cells-derived extracellular vesicles promote liver regeneration during acute liver failure.","authors":"Yi Chen, Yuling Wu, Hanyong Sun, Hongdan Zhang, Dan Tang, Tianjie Yuan, Caiyang Chen, Weijian Huang, Xu Zhou, Hongping Wu, Saihong Xu, Wenming Liu, Yingfu Jiao, Liqun Yang, Qigen Li, Hexin Yan, Weifeng Yu","doi":"10.1007/s10565-024-09954-6","DOIUrl":"10.1007/s10565-024-09954-6","url":null,"abstract":"<p><p>Hepatocyte-derived liver progenitor-like cells (HepLPCs) exhibit a remarkable capacity to support liver function by detoxifying ammonia, promoting native liver regeneration, and suppressing inflammation, which leads to improvements in the recovery and survival of animals with acute liver failure (ALF). However, the mechanism through which HepLPCs promote liver regeneration is unclear. Here, we isolated HepLPC-derived extracellular vesicles (HepLPC-EVs) from conditioned media and performed microRNA sequencing analysis. Our results showed HepLPC-EVs promoted liver regeneration in mice with carbon tetrachloride or acetaminophen induced ALF. Cell cycle progression and proliferation of primary human hepatocytes were promoted after coculture with HepLPC-EVs. Exosomal miRNA sequencing confirmed that HepLPC-EVs were enriched with miR-183-5p, which played an essential role in ameliorating ALF. Mechanistically, HepLPC-derived exosomal miR-183-5p negatively regulated the expression of the target gene FoxO1, activated the Akt/GSK3β/β-catenin signaling pathway, and thereby promoted liver regeneration and restoration of normal liver function. These results indicate that during ALF, HepLPC-Exos mediate liver regeneration mainly through a paracrine exosome-dependent mechanism and these effects accelerate liver regeneration and lead to the restoration of normal liver function.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"106"},"PeriodicalIF":5.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNF38 promotes gilteritinib resistance in acute myeloid leukemia via inducing autophagy by regulating ubiquitination of LMX1A.","authors":"Yiyun Pan, Wen Zeng, Ting Liang, Xiaoming Nie, Kang Liu, Hailong Chen, Nengping Luo, Xiaodan Zhu, Keqiang Tian, Yijian Chen","doi":"10.1007/s10565-024-09936-8","DOIUrl":"10.1007/s10565-024-09936-8","url":null,"abstract":"<p><strong>Background: </strong>Gilteritinib is a commonly used targeted drug for acute myeloid leukemia (AML), but the emergence of gilteritinib resistance greatly reduces the therapeutic effect. RING finger protein 38 (RNF38), a protein with RING Finger domain and E3 ubiquitin ligase activity, has been implicated in tumorigenesis and drug resistance. However, the role and mechanism of RNF38 in the gilteritinib resistance of AML remains unclear.</p><p><strong>Methods: </strong>Normal AML cells were treated with gilteritinib to construct gilteritinib-resistant cells (MV4-11/Gilteritinib and MOLM-13/Gilteritinib). CCK8 assay, TUNEL staining and EdU assay were used to assess gilteritinib resistance, cell apoptosis and proliferation. The protein levels of autophagy-related markers, RNF38 and LIM homeobox transcription factor 1 alpha (LMX1A) were determined by western blot. Also, RNF38 and LMX1A mRNA levels were tested using qRT-PCR. Autophagic flux was assessed using mRFP-GFP-LC3 labeling, and autophagosome numbers was counted under transmission electron microscopy. Co-IP assay was employed to analyze interaction between RNF38 and LMX1A. The effects of LMX1A and RNF38 on AML tumorigenesis were analyzed by in vivo experiments.</p><p><strong>Results: </strong>In gilteritinib-resistant AML cells, autophagy-related markers, mRFP-GFP-LC3 signals and autophagosome numbers were significantly enhanced. Autophagy inhibitor 3-MA could suppress gilteritinib resistance in AML cells. RNF38 knockdown inhibited gilteritinib resistance and autophagy in AML cells. Mechanistically, RNF38 reduced LMX1A expression by inducing its ubiquitination. RNF38 overexpression reversed the inhibitory effect of LMX1A on gilteritinib resistance and autophagy in AML cells, as well as AML tumor growth in vivo, while these effects could be abolished by proteasome inhibitor MG132.</p><p><strong>Conclusions: </strong>RNF38 induced autophagy to promote gilteritinib resistance in AML by increasing the ubiquitination of LMX1A.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"105"},"PeriodicalIF":5.3,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protocatechuic acid relieves ferroptosis in hepatic lipotoxicity and steatosis via regulating NRF2 signaling pathway.","authors":"Yetong Feng, Mengjiao Shi, Yi Zhang, Xinyan Li, Liangwen Yan, Jiayi Xu, Chenyue Liu, Miaomiao Li, Fengyun Bai, Fenyue Yuan, Ying Sun, Rongrong Liu, Yaping Zhao, Lan Yang, Yinggang Zhang, Ying Guo, Jian Zhang, Rui Zhou, Pengfei Liu","doi":"10.1007/s10565-024-09953-7","DOIUrl":"10.1007/s10565-024-09953-7","url":null,"abstract":"<p><p>Ferroptosis represents a newly programmed cell death, and the process is usually accompanied with iron-dependent lipid peroxidation. Importantly, ferroptosis is implicated in a myriad of diseases. Recent literature suggests a potential position of ferroptosis in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD), the most widespread liver ailment worldwide. Intriguingly, several functional genes and metabolic pathways central to ferroptosis are regulated by nuclear factor erythroid-derived 2-like 2 (NRF2). In current work, we aim to identify protocatechuic acid (PCA), a primary metabolite of antioxidant polyphenols, as a potent NRF2 activator and ferroptosis inhibitor in the hepatic lipotoxicity and steatosis models. Herein, both NRF2^+/+ and NRF2^-/- cell lines and mice were used to analyze the importance of NRF2 in PCA function, and hepatic lipotoxicity and steatosis models were induced by palmitic acid and high-fat diet respectively. Our results indicated that ferroptosis was mitigated by PCA intervention in hepatic cells. Furthermore, PCA exhibited therapeutic efficacy against ferroptosis, as well as hepatic lipotoxicity and steatosis. The protective role of PCA was predominantly mediated through NRF2 activation, potentially elucidating a pivotal mechanism underlying PCA's therapeutic impact on MAFLD. Additionally, the augmented mitochondrial TCA cycle activity observed in hepatic lipotoxicity and steatosis models was ameliorated by PCA, in part via NRF2-dependent pathways, further bolstering PCA's anti-ferroptosis properties. Collectively, our findings underscore PCA's potential in alleviating hepatic ferroptosis, lipotoxicity and steatosis via inducing activation of NRF2 signaling pathway, offering a promising strategy for the therapy of MAFLD as well as related lipid metabolic disorders.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"104"},"PeriodicalIF":5.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11599353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CREB3 protein family: the promising therapeutic targets for cardiovascular and metabolic diseases.","authors":"Yi-Peng Gao, Can Hu, Min Hu, Wen-Sheng Dong, Kang Li, Yun-Jia Ye, Yu-Xin Hu, Xin Zhang","doi":"10.1007/s10565-024-09939-5","DOIUrl":"10.1007/s10565-024-09939-5","url":null,"abstract":"<p><p>Significant advancements in cardiovascular and metabolic disease research have been made with the CREB3 protein family. Studies have revealed that members of this family are crucial in the development of these diseases, contributing to the regulation of lipid metabolism, inflammation, and vascular function. These studies provide useful information for future therapeutic strategies in cardiovascular and metabolic diseases.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"103"},"PeriodicalIF":5.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11586310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ASPP2 deficiency attenuates lipid accumulation through the PPARγ pathway in alcoholic liver injury.","authors":"Ying Zhang, Xingzhong Miao, Fang Liu, Honglin Shi, Dexi Chen, Yu Chen, Yingmin Ma, Hongbo Shi","doi":"10.1007/s10565-024-09925-x","DOIUrl":"10.1007/s10565-024-09925-x","url":null,"abstract":"<p><p>The initial stage of alcoholic liver disease (ALD) is hepatic steatosis. Recent studies have highlighted a possible role for Apoptosis-stimulating protein 2 of p53 (ASPP2) in regulating hepatic lipid metabolism in nonalcoholic fatty liver (NAFLD). However, whether ASPP2 regulates alcohol-induced lipid accumulation and its mechanisms remain unclear. To explore that, we establish an alcoholic liver injury model in vivo and in vitro. The clinical specimens were collected from liver tissues of patients with alcoholic liver disease. Lipid metabolism was detected by HE staining, oil red O staining and qPCR; and ASPP2-peroxisome proliferator-activated receptor γ (PPARγ) signaling pathways were detected by western blot and immunohistochemical staining. We found that both ASPP2 and PPARγ expression increased in patients and mouse models with ALD. We also discovered the reduction of ASPP2 significantly inhibited the expression of PPARγ and alleviated alcohol-induced hepatic lipid accumulation and liver injury in vivo and in vitro. Mechanistically, the PPARγ agonist reversed the protective effect of ASPP2 downregulation on hepatic steatosis and liver injury, while the opposite results were observed using PPARγ inhibitor. In conclusion, ASPP2 exacerbates ethanol-induced lipid accumulation and hepatic injury by upregulating the PPARγ signaling pathway, thus promoting the occurrence and development of ALD.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"102"},"PeriodicalIF":5.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11584427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing gastric cancer treatment: nanotechnology innovations and future prospects.","authors":"Tengfei Yang, Lin Guo","doi":"10.1007/s10565-024-09943-9","DOIUrl":"10.1007/s10565-024-09943-9","url":null,"abstract":"<p><p>Gastric cancer (GC) is the fifth most common cancer worldwide, particularly prevalent in Asia, especially in China, where both its incidence and mortality rates are significantly high. Meanwhile, nanotechnology has demonstrated great potential in the treatment of GC. In particular, nanodrug delivery systems have improved therapeutic efficacy and targeting through various functional modifications, such as targeting peptides, tumor microenvironment responsiveness, and instrument-based methods. For instance, silica (SiO₂) has excellent biocompatibility and can be used as a drug carrier, with its porous structure enhancing drug loading capacity. Polymer nanoparticles regulate drug release rates and mechanisms by altering material composition and preparation methods. Lipid nanoparticles efficiently encapsulate hydrophilic drugs and promote cellular uptake, while carbon-based nanoparticles can be used in biosensors and drug delivery. Targets such as integrins, HER2 receptors, and the tumor microenvironment have been used to improve drug efficacy in GC treatment. Nanodrug delivery techniques not only enhance drug efficacy and delivery capabilities but also selectively target tumor cells. Currently, there is a lack of systematic summarization and synthesis regarding the relationship between nanodrug delivery systems and GC treatment, which to some extent hinders researchers and clinicians from efficiently searching for and referencing related studies, thereby reducing work efficiency. This study aims to systematically summarize the existing research on the relationship between nanodrug delivery systems and GC treatment, making it easier for professionals to search and reference, and thereby promoting further research on the role of nanodrug delivery systems and their clinical applications in GC. This review discusses the applications of functionalized nanocarriers in the treatment of GC in recent years, including surface modifications with targeted markers, the combination of phototherapy, chemotherapy, and immunotherapy, along with their advantages and challenges. It also examines the future prospects of targeted nanomaterials in GC treatment. The review particularly focuses on the combined application of nanocarriers in multiple treatment modalities, such as phototherapy, chemotherapy, and immunotherapy, demonstrating their potential in multimodal treatments. Furthermore, it thoroughly explores the specific challenges that nanocarriers face in GC treatment, such as biocompatibility, drug release control, and clinical translation issues, while providing a systematic outlook on future developments. Additionally, this study emphasizes the potential value and feasibility of nanocarriers in clinical applications, contrasting with most reviews that focus on basic research. Through these innovations, we offer new perspectives and directions for the development of nanotechnology in the treatment of GC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"101"},"PeriodicalIF":5.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11579161/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pivotal role of ZNF384: driving the malignant behavior of serous ovarian cancer cells via the LIN28B/UBD axis.","authors":"Ye Yang, Runze He, Dongxiao Li, Tianli Mu, Ziteng Kuang, Min Wang","doi":"10.1007/s10565-024-09938-6","DOIUrl":"10.1007/s10565-024-09938-6","url":null,"abstract":"<p><p>Zinc finger protein 384 (ZNF384) is a highly conserved transcribed gene associated with the development of multiple tumors, however, its role and mechanism in serous ovarian cancer (SOC) are unknown. We first confirmed that ZNF384 was abnormally highly expressed in SOC tissues by bioinformatics analysis and immunohistochemistry. We further used lentivirus packaging and transfection techniques to construct ZNF384 overexpression or knockdown cell lines, and through a series of cell function experiments, gradually verified that ZNF384 promoted a series of malignant behaviors of SOC cell proliferation, migration, and invasion. By establishing a xenotransplantation model in nude mice, it was confirmed that ZNF384 promoted the progress of SOC in vivo. Mechanistically, Overexpression of ZNF384 enhanced the transcriptional activity of Lin-28 homolog B (LIN28B), which promoted the malignant behavior of SOC cells. In addition, LIN28B could regulate the expression of the downstream factor ubiquitin D (UBD) in SOC cells, further promoting the development of SOC. This study shows that ZNF384 aggravates the malignant behavior of SOC cells through the LIN28B/UBD axis, which may be used as a diagnostic biomarker for patients with SOC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"100"},"PeriodicalIF":5.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALKBH5 insufficiency protects against ferroptosis-driven cisplatin-induced renal cytotoxicity.","authors":"Yu Zhu, Yanyan Jin, Xue He, JunYi Chen, Yao Zhang, JingJing Wang","doi":"10.1007/s10565-024-09947-5","DOIUrl":"10.1007/s10565-024-09947-5","url":null,"abstract":"<p><p>In the clinical setting, cisplatin-induced nephrotoxicity primarily manifests as acute kidney injury (AKI). Recent studies have indicated that ferroptosis, a type of iron-dependent cell death, is closely involved in the cisplatin nephrotoxicity. AlkB homologue 5 (ALKBH5), an N6-methyladenosine (m6A) eraser protein expressed in various tissues, including the kidneys, has been implicated in this process. However, the specific role of ALKBH5 in cisplatin-induced nephrotoxicity remains unknown. Our findings indicated that ALKBH5 was upregulated in cisplatin-induced AKI, and the in vivo study results were consistent with the results of the in vitro study. Additionally, ALKBH5 knockout in transgenic animals was found to mitigate cisplatin-induced renal dysfunction, whereas its knock-in exacerbated the effects. Our study revealed that ALKBH5 controls the traditional ferroptosis metabolic pathway, leading to worsening of AKI in experiments conducted both in vivo and in vitro. The efficacy of pharmacological intervention targeting ALKBH5 in AKI animal models was demonstrated, and ALKBH5-based gene therapy confirmed these findings and displayed renoprotective effects against AKI. In conclusion, this study highlighted the crucial role of ALKBH5 as a key regulator of AKI. Overall, our research demonstrates the significant impact of ALKBH5 in controlling ferroptosis in cisplatin-induced AKI, suggesting that focusing on ALKBH5 could be a promising approach for treating cisplatin-related kidney damage.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"99"},"PeriodicalIF":5.3,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GRK2 mediates cisplatin-induced acute liver injury via the modulation of NOX4.","authors":"Qianlei Wang, Mengyang Li, Fei Duan, Kangjun Xiao, Qing Qing Sun, Jiang Rui Cheng, Lei Ni, Zhengkun Xu, Bingfa Xu, Feng Xiao, Jiajie Kuai, Wei Wei, Chun Wang","doi":"10.1007/s10565-024-09940-y","DOIUrl":"10.1007/s10565-024-09940-y","url":null,"abstract":"<p><strong>Background: </strong>The present study investigated the function of G protein-coupled receptor kinase 2 (GRK2) in acute liver injury (ALI) by cisplatin, and investigated the protective effect of pharmacological inhibition of GRK2.</p><p><strong>Methods: </strong>ALI models were generated in global adult hemizygous (ALI-Grk2^±) mice and wild-type (WT) mice. Liver biochemistry parameters and histopathology were used to evaluate the severity of ALI and the protective effect of pharmacological inhibition of GRK2. GRK2-siRNA was used to knock down the expression of GRK2 in AML12 cells in vitro.</p><p><strong>Results: </strong>ALI model mice exhibited increased blood levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and abnormal liver pathology accompanied by imbalanced L-glutathione (GSH) levels. Cisplatin administration upregulated GKR2, p-GRK2 and NADPH oxidase 4 (NOX4) expression in the liver tissues of ALI model mice. Compared to WT mice injected with cisplatin, Grk2^± mice that received cisplatin showed significant improvements in liver function and pathological performance, decreased NOX4 levels, reduced endoplasmic reticulum (ER) stress, and diminished liver cell apoptosis. In vitro, the transfection of AML12 cells with siRNA significantly reduced NOX4 expression and inhibited cisplatin-induced reactive oxygen species production, ER stress (increased levels of GRP94, GRP78, p-elF2α and CHOP) and apoptotic death. Moreover, pharmacological treatment with drugs that inhibit GRK2 (CP-25 or paroxetine) significantly ameliorated cisplatin-induced ALI by improving liver pathological manifestations, inhibiting oxidative stress and ER stress, and reducing liver cell apoptosis. Similar results were observed in vitro.</p><p><strong>Conclusions: </strong>GRK2 mediates the development of cisplatin-induced ALI by modulating NOX4 and ER stress. Pharmacological inhibition of GRK2 with CP-25 or paroxetine effectively alleviated ALI. GRK2 can be used as a potential target for the prevention and treatment of liver injury.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"40 1","pages":"98"},"PeriodicalIF":5.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11567994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}