Acta biochimica et biophysica Sinica最新文献

{"title":"HK2-mediated augmentation of endothelial cell glycolysis promotes placental vascular disorders through lactylation and pyroptosis.","authors":"Xiujing Lu, Yu Long, Menglian Liao, Xiaoqian Fu, Min Wu, Lu Xiao, Guining He, Yachang Zeng","doi":"10.3724/abbs.2025124","DOIUrl":"https://doi.org/10.3724/abbs.2025124","url":null,"abstract":"<p><p>Preeclampsia (PE) involves complex metabolic-inflammatory interactions, yet the mechanistic links among glycolysis, protein lactylation, and pyroptosis in placental pathogenesis remain undefined. In this study, we explore their tripartite relationship with PE development by combining bioinformatics analysis of PE-associated transcriptomes with experimental validation using placental tissues from PE patients and healthy controls. To elucidate the underlying mechanism, we utilize <i>in vitro</i> models involving hypoxic endothelial cell cultures, pharmacological glycolysis inhibition via 2-deoxyglucose, and genetic modulation of hexokinase 2 (HK2) expressions through siRNA silencing and plasmid-based overexpression. Molecular profiling is used to assess the expressions of key glycolytic enzymes, lactylation markers, and pyroptosis-related factors. Compared with control placental tissues, PE placental tissues present significantly higher expressions of glycolytic enzymes, elevated protein lactylation levels, and increased pyroptosis markers. Similarly, hypoxic endothelial cells exhibit coordinated upregulation of these three pathways. Notably, pharmacological glycolysis inhibition significantly reduces both lactylation and pyroptosis levels. Genetic experiments further demonstrate that <i>HK2</i> silencing decreases glycolytic activity, subsequently attenuating lactylation and pyroptosis, whereas HK2 overexpression has opposite effects, underscoring its central regulatory role in this metabolic-inflammatory axis. Collectively, these findings indicate that HK2-mediated glycolysis drives placental vascular endothelial lactylation and pyroptosis, revealing a novel mechanistic pathway in PE pathophysiology.</p>","PeriodicalId":6978,"journal":{"name":"Acta biochimica et biophysica Sinica","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LINC00114 promotes colorectal cancer metastasis by targeting HNRNPA1 to regulate glutamine metabolism reprogramming and angiogenesis.","authors":"Shiyu Tang, Meng Liu, Yangyang Zhu, Lifa Li, Chen Qing, Yuehua Guan, Tong Zhou, Xuegui Tang","doi":"10.3724/abbs.2025141","DOIUrl":"https://doi.org/10.3724/abbs.2025141","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a common type of gastrointestinal malignancy, and it has a close connection with long noncoding RNAs (lncRNAs). This study aims to examine the involvement of long noncoding RNA LINC00114, which targets heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) in regulating glutamine metabolism and angiogenesis in the metastasis of colorectal cancer (CRC). LINC00114 and HNRNPA1 levels are measured in CRC tissues and cells to determine their expression levels. Then, siRNA targeting LINC00114 (si-LINC00114) is used to transfect CRC cells, and cell proliferation and metastasis are detected. The influence of exogenous glucose and glutamine supplementation on angiogenesis induced by LINC00114 in CRC is investigated in HUVECs. Glutamine metabolism in CRC cells is also detected. Furthermore, the role of LINC00114 in CRC xenograft tumors is studied <i>in vivo</i>. LINC00114 and HNRNPA1 are highly expressed in CRC and positively correlate with CD31. si-LINC00114 significantly inhibits proliferation, metastasis and HNRNPA1 expression in CRC cells. An RNA-binding-protein immunoprecipitation (RIP) assay confirms that LINC00114 can bind to HNRNPA1 and positively regulate its expression. Further experiments confirm that si-LINC00114 significantly inhibits cell proliferation and tubule formation in HUVECs. Exogenous glucose and glutamine supplementation significantly promotes the levels of LINC00114 and HNRNPA1 in CRC cells and promotes tubule formation in HUVECs. In addition, transfection of CRC cells with si-LINC00114 and/or oe-HNRNPA1 regulates glutamine metabolism in CRC cells. Animal studies confirm that intervention with LINC00114 represses the progression and vascular normalization of CRC and regulates glutamine metabolism. In conclusion, LINC00114 promotes CRC metastasis by targeting HNRNPA1 to regulate glutamine metabolic reprogramming and angiogenesis.</p>","PeriodicalId":6978,"journal":{"name":"Acta biochimica et biophysica Sinica","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy-dependent sensitization effects of PARP inhibitors on recurrent nasopharyngeal carcinoma treated with carbon ion and photon irradiation.","authors":"Ziyu Le, Haojiong Zhang, Li Chen, Wanzun Lin, Qingting Huang, Shikai Geng, Wei Hu, Huaiyuan Chen, Fangzhu Wan, Xingyu Liu, Jiyi Hu, Fengtao Su, Jiade J Lu, Lin Kong","doi":"10.3724/abbs.2025130","DOIUrl":"https://doi.org/10.3724/abbs.2025130","url":null,"abstract":"<p><p>Tumor radioresistance and severe toxicity make reirradiation for recurrent nasopharyngeal carcinoma (NPC) a significant clinical challenge. This study aims to investigate the ability of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib to sensitize recurrent NPC cells irradiated with photon or carbon ion (C-ion), and to explore the underlying mechanism of the synergistic promotion of cell death by olaparib and ionizing radiation. The results show that olaparib has significant X-ray and C-ion radiosensitization effects on recurrent NPC cells and the associated HK-RR photon-resistant model. Radiation, particularly C-ion exposure, induces a homologous recombination (HR)-deficient gene signature in HR-proficient NPC cells, potentially increasing their sensitivity to PARP inhibition. C-ion and X-ray irradiation induces similar modes of cell death, and multiple cell death pathways (including apoptosis, necrosis, ferroptosis, senescence, and autophagic cell death (ACD)) contribute to the cytotoxic effects of radiation combined with olaparib, with ACD being the dominant pathway. Both the pharmacological and genetic inhibition of autophagy significantly attenuate the radiosensitization effect of olaparib. In conclusion, olaparib effectively sensitizes recurrent NPC cells to both X-ray irradiation and C-ion irradiation, with autophagy playing a central role in mediating this effect.</p>","PeriodicalId":6978,"journal":{"name":"Acta biochimica et biophysica Sinica","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FSCN1-mediated hepatic gluconeogenesis is indispensable for neonatal mice survival.","authors":"Xiangxiang Liu, Yuanzhao Hu, Liangwei Wu, Yiwen Zhang, Lei Sang, Yake Gao, Lei He, Wenyong Xiong, Shengyu Yang, Jianwei Sun","doi":"10.3724/abbs.2025146","DOIUrl":"https://doi.org/10.3724/abbs.2025146","url":null,"abstract":"<p><p>Actin-bundling protein Fascin1 (FSCN1) is encoded by the <i>Fscn1</i> gene and is crucial for cytoskeletal remodeling and cellular migration. Although a previous study linked <i>Fscn1</i> deficiency to neonatal lethality in mice, the underlying metabolic mechanism remains unclear. In this study, we report that systemic knockout (KO) of <i>Fscn1</i> leads to 52.2% mortality within 24 h post-birth, accompanied by severe hypoglycemia in KO pups compared with their littermates. Remarkably, this lethality is fully rescued by oral glucose administration, indicating a glucose supply-dependent survival mechanism. Surviving <i>Fscn1</i>-KO neonates display persistent developmental deficits, including growth retardation and depleted lipid stores, despite intact canonical insulin-regulated hepatic gluconeogenic pathways. Transcriptomic profiling of P0 livers reveals that <i>Fscn1</i> loss predominantly disrupts metabolic pathways, with the glycerol phosphate shuttle being the most significantly downregulated module. Mechanistically, <i>Fscn1</i>-KO livers exhibit markedly reduced protein levels of glycerol-3-phosphate dehydrogenase isoforms (GPD1/GPD2), key enzymes bridging glycolysis and gluconeogenesis. Consistently, glycerol tolerance tests demonstrate impaired glycerol-to-glucose conversion in <i>Fscn1</i>-KO mice, confirming defective glycerol-driven gluconeogenesis. Our findings establish FSCN1 as a novel cytoskeletal-metabolic integrator essential for neonatal survival by sustaining hepatic glucose production from glycerol, thus revealing an unexpected role of actin dynamics in coordinating metabolic adaptation during early postnatal development.</p>","PeriodicalId":6978,"journal":{"name":"Acta biochimica et biophysica Sinica","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic potential of dihydrocapsaicin in vascular smooth muscle cell calcification.","authors":"Chenxi Li, Jiajun Chen, Zhiqing Liu, Hongling Zhu, Zeyu Huang, Qingyun Zhu, Lianyong Liu, Chaobao Zhang, Xiangqi Li","doi":"10.3724/abbs.2025143","DOIUrl":"https://doi.org/10.3724/abbs.2025143","url":null,"abstract":"","PeriodicalId":6978,"journal":{"name":"Acta biochimica et biophysica Sinica","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring DNA topoisomerase II alpha in adrenocortical carcinoma through multi-omics analysis: a potential biomarker and therapeutic target.","authors":"Jianming Lu, Pei Deng, Zhenjie Wu, Yuxiang Liang, Yangjia Zhuo, Yongding Wu, Yingke Liang, Jianheng Ye, Wenjie Xie, Zhouda Cai, Chao Cai, Jiahong Chen, Le Zhang, Junhong Deng, Weide Zhong, Jiaojiao Tang, Zhaodong Han","doi":"10.3724/abbs.2025144","DOIUrl":"https://doi.org/10.3724/abbs.2025144","url":null,"abstract":"<p><p>Adrenocortical carcinoma (ACC) is a rare but aggressive cancer. Recent studies identified DNA Topoisomerase II Alpha (TOP2A) as a potential biomarker for ACC, which can provide new avenues for targeted therapy and improve clinical outcomes. This study aims to elucidate the role of TOP2A in ACC by exploring its prognostic value and identifying inhibitors for ACC therapy. Utilizing RNA sequencing data, mutation data, and clinical information from The Cancer Genome Atlas (TCGA-ACC) and additional datasets from the Gene Expression Omnibus (GEO), differential expression and prognostic analyses are conducted to assess the significance of TOP2A in ACC. Immunohistochemistry and cell assays, including cell viability, colony formation, and transwell assays, are conducted to validate the oncogenic effects of TOP2A. The \"IOBR\" R package is used to examine the relationship between TOP2A expression and CD8 ⁺ T-cell infiltration. The CMap platform is used to identify potential TOP2A inhibitors. <i>In vivo</i> assays verify the therapeutic effect of TOP2A inhibitors on ACC. Our findings indicate that TOP2A is significantly overexpressed in ACC and is associated with poor prognosis. Immunohistochemistry and cell assays confirm the oncogenic role of TOP2A. Furthermore, distinct gene expression patterns related to different TOP2A expression levels are identified, influencing the response to immunotherapy. Potential inhibitors targeting TOP2A are discovered, and the therapeutic effects of resminostat and etoposide are confirmed via <i>in vivo</i> assays, suggesting new therapeutic strategies for ACC treatment. In conclusion, TOP2A serves as a crucial biomarker in ACC and is associated with adverse clinical outcomes and a diminished immune response. The identification of potential inhibitors against TOP2A opens new avenues for the development of targeted therapies for ACC patients.</p>","PeriodicalId":6978,"journal":{"name":"Acta biochimica et biophysica Sinica","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DDX11 interacts with PARP1 to facilitate PARylation, thereby promoting gallbladder cancer progression and conferring gemcitabine resistance.","authors":"Yuan Gao, Junchi Liu, Xiang Yao, Letian Gong, Shubin Luo, Chaoxian Zhao, Shaofeng Pu, Ganglong Gao","doi":"10.3724/abbs.2025155","DOIUrl":"https://doi.org/10.3724/abbs.2025155","url":null,"abstract":"<p><p>Gemcitabine resistance poses a significant challenge in gallbladder cancer (GBC) treatment, necessitating exploration of its molecular mechanisms. This study focuses on DDX11, which is highly expressed in gemcitabine-resistant GBC cells, suggesting a potential role in DNA damage repair. We establish gemcitabine-resistant GBC cell lines and observe significantly higher DDX11 expression in these cells than in parental cells. Clinical tissue analysis through qRT-PCR, western blot analysis, and immunohistochemistry confirms elevated DDX11 levels in tumors compared with adjacent normal tissues. Functional assays demonstrate that <i>DDX11</i> knockdown inhibits cell proliferation, colony formation, and tumor growth, while restoring gemcitabine sensitivity. Mechanistically, proteomic analysis and co-immunoprecipitation reveal that the interaction of DDX11 with PARP1 leads to increased poly(ADP-ribosyl)ation (PARylation), which promotes DNA repair and drug resistance. Notably, combining gemcitabine with the PARP inhibitor olaparib has synergistic anti-tumor effects on resistant cells. These findings indicate that DDX11 contributes to GBC progression and chemoresistance by regulating PARP1-mediated PARylation and that targeting this pathway with PARP inhibitors may overcome gemcitabine resistance. This study provides new insights into GBC drug resistance mechanisms and suggests that combining conventional chemotherapy with PARP inhibition is a potential therapeutic strategy for resistant patients. The DDX11-PARP1-PARylation axis represents a promising target for improving GBC treatment outcomes, particularly in gemcitabine-resistant patients.</p>","PeriodicalId":6978,"journal":{"name":"Acta biochimica et biophysica Sinica","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"L-arginine synergistic with 5-fluorouracil intervenes in DNA damage repair via the DNA-PKcs/ATM/ATR pathway in hepatocellular carcinoma cells.","authors":"Han Wang, Huaxia Xie, Yuan Lin, Zhixin Zhang, Miaoqi Zhang, Junjie Zhao, Qingzan Zhao, Ling Liu","doi":"10.3724/abbs.2025137","DOIUrl":"https://doi.org/10.3724/abbs.2025137","url":null,"abstract":"<p><p>DNA damage repair is a critical physiological process. The combined treatment of L-Arg and 5-FU significantly inhibits cell proliferation, enhances nitric oxide (NO) production via inducible nitric oxide synthase (iNOS), and promotes the accumulation of reactive oxygen species (ROS). This heightened oxidative stress triggers DNA damage and apoptosis, as evidenced by a substantial increase in the Bax/Bcl-2 ratio; the activation of caspase-9, caspase-3, and PARP cleavage; and increased level of phosphorylated p53. Moreover, the combination treatment induces G2/M phase arrest, with a significant increase in p-H2AX (Ser 139) (known as γ-H2AX) expression, indicating extensive DNA damage. Mechanistically, the combined treatment modulates DNA damage response pathways by downregulating DNA-PKcs. Concurrently, it enhances the phosphorylation of ATM, ATR, CHK1, CHK2, and BRCA1. Additionally, the L-Arg and 5-FU combination downregulates PI3K/AKT signaling. AZD-7648 (a DNA-PKcs inhibitor) and LY294002 (a PI3K inhibitor) enhance p-ATM and p-ATR activation, resulting in elevated apoptosis and increased γ-H2AX expression. In contrast, the inhibition of ATM/ATR by CGK733 suppresses this response, reducing apoptosis and DNA damage signaling. Additionally, the ROS scavengers NAC and iNOS, when applied separately, restore p-AKT and DNA-PKcs expression; suppress the upregulation of p-ATM, p-ATR, and γ-H2AX; and ultimately reduce apoptosis. These findings are validated in a DEN-induced rat liver cancer model. In summary, 5-FU and L-Arg synergistically increase iNOS/NO-driven ROS accumulation, inducing γ-H2AX-marked DNA damage through dual modulation of repair pathways (inhibiting PI3K/AKT/DNA-PKcs while activating ATM/ATR), ultimately triggering p53-mediated G2/M arrest and apoptosis in hepatocellular carcinoma cells.</p>","PeriodicalId":6978,"journal":{"name":"Acta biochimica et biophysica Sinica","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the mechanisms underlying sulfasalazine-induced ferroptotic cell death: role of protein disulfide isomerase-mediated NOS activation and NO accumulation.","authors":"Yi-Chen Jia, Jia-Ling Zhong, Xiangyu Hao, Bao Ting Zhu","doi":"10.3724/abbs.2025100","DOIUrl":"https://doi.org/10.3724/abbs.2025100","url":null,"abstract":"<p><p>Sulfasalazine (SAS), a clinically utilized anti-inflammatory drug, has been shown to induce ferroptosis by inhibiting system Xc ^- activity, thereby causing cellular glutathione depletion. Recently, protein disulfide isomerase (PDI) was shown to be an upstream mediator of the oxidative cell death (oxytosis/ferroptosis) induced by glutamate, erastin, RSL3 and SAS. The present study aims to further characterize the detailed biochemical and cellular mechanisms of SAS-induced ferroptosis in two cell lines, <i>i</i>. <i>e</i>., H9C2 rat cardiomyocytes and BRL-3A rat hepatocytes, with a focus on elucidating the critical role of PDI in mediating SAS-induced toxicity. We find that SAS can induce ferroptosis in H9C2 and BRL-3A cells, which is accompanied by a sequential increase in the buildup of cellular nitric oxide (NO), reactive oxygen species (ROS) and lipid-ROS. SAS activates PDI-mediated dimerization of inducible NO synthase (iNOS) and cellular accumulation of NO, and these effects are followed by ROS and lipid-ROS accumulation. Furthermore, SAS markedly upregulates the iNOS protein levels in these cells. Knockdown of <i>PDI</i> or pharmacological inhibition of PDI catalytic activity effectively suppresses SAS-induced iNOS dimerization, abrogates SAS-induced accumulation of NO, ROS and lipid-ROS, and prevents ferroptosis. On the other hand, PDI activation through the use of TrxR1 inhibitors sensitizes these cells to SAS-induced ferroptosis. These findings provide further experimental support for a pivotal role of PDI in SAS-induced cytotoxicity through the activation of the PDI-NOS-NO axis, which then leads to the accumulation of cellular ROS and lipid-ROS and ultimately the induction of oxidative cell death.</p>","PeriodicalId":6978,"journal":{"name":"Acta biochimica et biophysica Sinica","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scutellarin inhibits ferroptosis by promoting cellular antioxidant capacity through regulating Nrf2 signaling.","authors":"Haiyan Yang, Onkei Chan, Xiaodi Huang, Liang Yan, Nuo Sun, Yaping Li, Zijian Shi, Qingbing Zha, Dongyun Ouyang, Jinhua Li, Xianhui He","doi":"10.3724/abbs.2025112","DOIUrl":"10.3724/abbs.2025112","url":null,"abstract":"<p><p>Ferroptosis is a lytic form of regulated cell death that is driven by iron-dependent lipid peroxidation and has been implicated in various diseases, including acute kidney injury (AKI). Scutellarin is a flavonoid isolated from <i>Erigeron breviscapus</i> (Vant.) Hand.-Mazz. and possesses various pharmacological activities, including anti-inflammatory and antioxidative properties. However, it is unclear whether scutellarin can inhibit ferroptosis and mitigate related diseases. In this study, we show that scutellarin can inhibit ferroptosis in both human HK-2 cells and mouse bone marrow-derived macrophages stimulated with RSL3 or erastin. Mitochondrial dysfunction and reactive oxygen species generation are counteracted by scutellarin treatment, suggesting the involvement of its antioxidative activity. Furthermore, scutellarin increases the nuclear levels of Nrf2 and the expressions of its target genes, including <i>HO-1</i> and <i>GPX4</i>. Scutellarin-mediated inhibition of ferroptosis and increases in these proteins are abrogated by co-treatment with brusatol, an Nrf2 inhibitor, indicating an essential role for Nrf2 in this process. In a mouse model of folic acid-induced AKI, scutellarin mitigates acute renal damage, as revealed by histopathological analysis and serum blood urea nitrogen and creatinine assays. Folic acid-induced acute renal injury is associated with increased ferroptosis, as revealed by elevated level of 4-hydroxynonenal (4-HNE), a surrogate marker of ferroptosis, which is diminished by scutellarin co-treatment. Specifically, the elevated 4-HNE levels in macrophages (MAC-2 positive) and other renal cells are suppressed by scutellarin. Overall, scutellarin can inhibit ferroptosis both in cultured cells and in a mouse model of AKI by regulating Nrf2 signaling.</p>","PeriodicalId":6978,"journal":{"name":"Acta biochimica et biophysica Sinica","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}