Cell Death Discovery
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2024
·Vol. 10
·期 1
·1-11
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IF 6.1
Zheng Guopei,Shi Jiahao,Li Qian,Jin Xiaoliang,Fang Yan,Zhang Zhe,Cao Qin,Zhu Lili,Shen Jianfeng
BRCA1-associated protein 1 (BAP1) acts as a tumor suppressor and can affect the cell cycle, tumor immunity, and cellular metabolism through multiple pathways. In melanoma, BAP1 mutations promote tumor cell glycolysis, leading to increased lactate production. The tumor microenvironment with high lactate levels is often associated with immunosuppression and tumor progression. The inhibitory effect of BAP1 on glycolysis has been found in a variety of tumors, but the specific mechanism by which BAP1 inhibits lactate production still needs to be elucidated. In this study, we show that BAP1 can interact directly with lactate dehydrogenase (LDHA), causing LDHA to accumulate in the nucleus. Conversely, BAP1 deletion leads to the accumulation of LDHA in the cytoplasm, catalyzing the production of lactate from pyruvate that results in increased lactate levels inside and outside the cell. By elucidating the interaction between BAP1 and LDHA and the subsequent effects on lactate production in melanoma cells, this work provides insights into the mechanism of BAP1-mediated metabolic regulation. Furthermore, it may provide novel directions for the clinical treatment of BAP1-mutant melanoma.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症代谢
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2019
·Vol. 20
·期 24
·6239
·
IF 4.183
Yu-Jiao Liu,Xiao-Yang Fan,An-Dong Wang,Yin-Zheng Xia,Wen-Rong Fu,Jun-Yi Liu,Feng-Lei Jiang,Yi Liu
Based on the potential therapeutic value in targeting metabolism for the treatment of cancer, an organic arsenical PDT-BIPA was fabricated, which exerted selective anti-cancer activity in vitro and in vivo via targeting lactate dehydrogenase A (LDHA) to remodel the metabolic pathway. In details, the precursor PDT-BIPA directly inhibited the function of LDHA and converted the glycolysis to oxidative phosphorylation causing ROS burst and mitochondrial dysfunction. PDT-BIPA also altered several gene expression, such as HIF-1α and C-myc, to support the metabolic remodeling. All these changes lead to caspase family-dependent cell apoptosis in vivo and in vitro without obvious side effect. Our results provided this organic arsenical precursor as a promising anticancer candidate and suggested metabolism as a target for cancer therapies.Keywords:organic arsenicals;lactate dehydrogenase A;metabolism;ROS;mitochondria;apoptosis
研究领域:
肿瘤学
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药理学
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分子生物学
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高影响因子
Frontiers in Oncology
·
2026
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IF 3.4
Bixia Chi,Zhi Cui,Xinyue Hou,Hongfang Ding,Linjun Li,Rui Ai,Yizhuang Yang,Yue Zhao,Liyan Wang,Juan Wang
Acidic leucine-rich nuclear phosphoprotein 32A(ANP32A) is known to possess multi-functions and has been observed to exhibit different roles across various malignancies. Although the expression of ANP32A has been shown to correlate with metastatic spread and reduced survival in Hepatocellular carcinoma(HCC), the underlying mechanisms have not been fully elucidated. This study utilized univariate Cox regression, differential gene analysis, and WGCNA to identify ANP32A as closely associated with poor HCC prognosis. Our Co-IP results confirmed the interaction between ANP32A and LDHA. Additionally, silencing ANP32A inhibited HCC cell proliferation in vitro as well as in vivo, and altered glycolytic and ferroptotic pathways, with increased LDHA ubiquitination detected. These data suggested that ANP32A may play a role in HCC progression, positioning it as a highly attractive therapeutic target for advanced HCC. Silencing ANP32A augmented the susceptibility of HCC cells to ferroptosis and inhibited aerobic glycolysis, which may provide new avenues for combination therapies, offering potential for improved patient outcomes.
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Advanced Science
·
2026
·
IF 14.1
Hui Wang,Mengyu Zhang,Weipeng Gong,Jiaxuan Wu,Junping Zhang,Wenxiu Zhang,Yue Liu,Kui Wang,Canhua Huang,Jun Zhou,Sijin Wu,Yan Li,Tianliang Li
Signal transducer and activator of transcription 3 (STAT3) activation is crucial in intestinal inflammation and tumorigenesis. However, its metabolic regulation is not well understood. Herein, we identified a macrophage-dependent methionine-S-adenosylmethionine (SAM)-protein arginine methyltransferase 1 (PRMT1)-lactate dehydrogenase A (LDHA)-lactate axis that controls intestinal inflammation through STAT3 regulation. Specifically, SAM promoted STAT3 Y705 phosphorylation and upregulated anti-inflammatory interleukin-10 expression in macrophages. Additionally, genetic ablation of PRMT1 in myeloid cells not only impairs STAT3 activation but also exacerbates colitis and promotes inflammation-associated tumorigenesis. Mechanistically, PRMT1 directly methylates LDHA at R268/R269, thereby enhancing its activity and lactate production. Subsequently, the resulting lactate induces STAT3 lactylation at K709, stabilizing an open conformation that facilitates Y705 phosphorylation. Importantly, disruption of this modification through K709-specific inhibition effectively blocks STAT3 activation and, consequently, exacerbates colitis progression. Overall, this study reveals STAT3 lactylation as a novel post-translational modification that integrates methionine metabolism with glycolytic flux to regulate intestinal inflammation, highlighting the critical role of immunometabolism in colonic inflammation.
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高影响因子
TISSUE & CELL
·
2026
·
IF 2.5
Xu Chen,Jianxing Liu,Yongrui Liang,Zihan Gong
Endometrial cancer (EC) is a common gynecological malignancy characterized by abnormal glucose metabolism. Paeonol (Pae), a natural phenolic compound derived from traditional Chinese medicine, exhibits broad-spectrum antitumor activity. However, its role in modulating glycolysis and the underlying molecular mechanisms in EC remain poorly understood. The effects on EC cell viability (CCK-8), proliferation (EdU), apoptosis (flow cytometry), invasion (transwell), migration (wound healing), and tube formation rate were assessed. Glycolytic parameters were measured using corresponding commercial kits. Protein and mRNA expression levels were determined by Western blotting and RT-qPCR. The interaction between tripartite motif protein 26 ( TRIM26) and lactate dehydrogenase A (LDHA) was investigated through co-immunoprecipitation (Co-IP), cycloheximide (CHX) chase, and ubiquitination assays. A xenograft model was established to examine the in vivo efficacy of Pae. Pae inhibited proliferation, metastasis, tube formation, and glycolysis of EC cells, and induced apoptosis. Pae suppressed EC malignant behaviors by downregulating LDHA expression. TRIM26 promoted ubiquitination-mediated degradation of LDHA. Overexpression of LDHA reversed the tumor-suppressive effects of TRIM26 overexpression in EC cells. TRIM26 knockdown attenuated the antitumor effects of Pae. In vivo experiments demonstrated that Pae inhibited tumor growth and regulated TRIM26/LDHA expression. Pae was found to promote TRIM26 expression, which in turn enhanced TRIM26-mediated ubiquitination and degradation of LDHA, thereby contributing to glycolysis inhibition and suppression of EC progression. These results suggested that Pae might exert its effects by modulating the TRIM26/LDHA axis and supported its potential therapeutic value in EC.
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高影响因子
MOLECULES
·
2026
·Vol. 31
·期 19
·3575
·
IF 5.1
Xinran Wang,Ruixue Huang,Gan Yang,Yuxia He,Shi Yin
Salidroside is a bioactive compound extracted from the traditional Chinese medicinal plantRhodiola roseathat exerts differential regulatory effects on cell viability depending on cell type and physiological state. Sertoli cells are important testicular somatic cells that play multiple roles in nourishing, protecting, and supporting spermatogenic cells. Currently, the regulatory effects and underlying mechanisms of salidroside on Sertoli cells remain unclear. This study investigated the effects of different concentrations of salidroside on the viability and regulatory mechanisms of TM4 cells (mouse Sertoli cell line). The results showed that within the range of 25–600 μM, cell viability decreased with increasing salidroside concentration. Treatment with 600 μM salidroside inhibited proliferation, promoted apoptosis, and suppressed the expression of key genes related to Sertoli cell function. Transcriptome sequencing revealed that several glycolysis-related genes, includingLdha,Pfkl,Eno3, andEno1b, were significantly downregulated in salidroside-treated cells, accompanied by marked reductions in key glycolytic metabolites, including fructose-1,6-diphosphate (FDP), pyruvate, lactic acid, and ATP. Notably, overexpression of lactate dehydrogenase A (Ldha) rescued cell viability and proliferation, suppressed apoptosis, elevated both intracellular and extracellular lactate and ATP levels, and partially restored functional gene expression in 600 μM salidroside-treated cells. Overall, this study provides hitherto undocumented evidence of the regulatory effects and mechanisms of salidroside on TM4 cells, identifying theLdha–glycolytic axis as an in vitro cellular target of high-dose salidroside in Sertoli cells, which may inform future in vivo reproductive safety profiling pending pharmacokinetic validation.
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Biology Direct
·
2025
·Vol. 20
·期 1
·1-15
·
IF 4.9
Wei Xiaoyong,Zou Long,Huang Yanqing,Qiu Chuan,Cheng Guang,Chen Ye,Rao Jun
Background Hepatocellular carcinoma (HCC) is among the deadliest cancers globally. Yes-Associated Protein (YAP), a Hippo pathway effector, crucially regulates cell proliferation and apoptosis. Recent research has implicated YAP’s role in HCC progression, but the mechanisms are unclear. This study aims to clarify YAP’s function in HCC, emphasizing its regulation of key pathways and targets. Results Gene knockout and overexpression models were established in nude mice and cell lines of HCC cells to investigate YAP’s impact on tumorigenesis. Additionally, functional assays and molecular biology techniques were employed to identify YAP’s regulatory networks. The study demonstrates that LDHA-regulated lactate production promotes YAP activation and malignant phenotypes in HCC. Overexpression of LDHA in HepG2 and Huh7 cells increased lactate levels and activated the YAP pathway, enhancing cell proliferation, migration, and invasion. Lactate treatment also promoted these malignant phenotypes by inhibiting YAP phosphorylation at Ser127. In a xenograft model, lactate accelerated tumor growth through YAP activation. YAP lactylation at K102 antagonized its Ser127 phosphorylation, further promoting malignant progression. Conclusions This study highlights the significance of YAP in HCC pathogenesis, providing insights into potential therapeutic targets for HCC management. Graphical
研究领域:
肿瘤学
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分子生物学
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高影响因子
CANCER LETTERS
·
2026
·
IF 11.8
Huaning Li,Run Shi,Yapeng Gao,Xing Cheng,Zhichao Wang,Yu Gao,Zhumei Shi,Mengjie Guo,Yongping You,Xiefeng Wang
Meningioma is the most common central nervous system tumor and high-grade tumors frequently show progressive growth or recurrence, posing substantial therapeutic challenges. However, the lack of effective chemotherapy and targeted therapies contributes to poor prognoses in patients with high-grade disease. In this study, we evaluated KRT18 expression in meningiomas and examined its correlation with patient prognosis using RNA sequencing and immunofluorescence staining. The oncogenic role of KRT18 in high-grade meningioma was further investigated using IOMM-Lee and CH157-MN cells, xenograft mouse models, and paraffin-embedded meningioma tissue sections. Finally, small-molecule inhibitors targeting KRT18-related mechanisms were explored. Analysis of clinical specimens across different meningioma grades demonstrated that KRT18 overexpression is associated with more advanced clinical features and poorer prognosis. Functional studies showed that KRT18 promotes meningioma cell proliferation and facilitates cell cycle progression by activating the PI3K/AKT signaling pathway. Mechanistically, KRT18 interacted with LDHA, an upstream regulator of PI3K/AKT signaling, and enhanced LDHA stability via inhibition of ubiquitination, which drives oncogenic growth by activating glycolysis and the PI3K/AKT signaling pathway. These findings were corroborated in a xenograft model. Finally, Fluvastatin was identified as a novel inhibitor that specifically targets the interaction between KRT18 and LDHA, thereby inhibiting meningioma proliferation by suppressing glycolysis and PI3K/AKT signaling. Collectively, these findings indicate that KRT18 serves as a potential diagnostic, prognostic, aggressiveness-related, and potential grading biomarker. It also functions as an oncogene by activating glycolysis and the PI3K/AKT signaling pathway through interaction with LDHA. Additionally, Fluvastatin is identified as a candidate for drug repurposing in high-grade meningioma.
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高影响因子
Evidence-based Complementary and Alternative Medicine
·
2022
·
IF 2.65
Ya Chen,Yuan Jiang,Xinyu Huang,Lin Chen,Hao Yang,Jian Zhao,Beibei Liang
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China, with a high incidence and mortality rate. Glucose metabolism reprogramming is a major characteristic of tumor cells. Increasing evidence indicates that aerobic glycolysis is associated with tumor growth and insensitivity to chemotherapy. Cordycepin inhibits the growth of HCC cells, but the mechanism is yet to be elucidated. Herein, in vitro and in vivo methods were utilized to investigate the cordycepin-inhibited growth of HCC by regulating the metabolic pathway of aerobic glycolysis. In vitro analyses using colony formation and flow cytometry revealed that cordycepin inhibits HCC cells’ proliferation and promotes apoptosis. In addition, cordycepin reduced the production of lactic acid and pyruvate, reduced the uptake of glucose, and decreased the extracellular acidification in HCC cells. Specifically, cordycepin inhibited the expression of HK2, LDHA, and PKM2 in aerobic glycolysis via the AMPK-Akt pathway. Taken together, these findings revealed that cordycepin reduces the tumor energy supply and decreases lactic acid production, thereby inhibiting the growth of HCC cells by regulating the metabolic pathway of aerobic glycolysis. These findings might provide novel insights into the mechanisms underlying cordycepin-mediated inhibition of tumor growth as well as a new treatment for HCC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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药理学
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高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Showkat Ali Ganie,Rayees Ahmad Naik,Ovas Ahmad Dar,Luqman Jameel Rather,Mohammed A. Assiri,Qing Li
We developed a facile method for the fabrication of a biodegradable delivery system composed of two blocks: curdlan and curcumin. This was achieved by chemical functionalization of curdlan through tosylation, amination followed by complexation with curcumin. A comprehensive evaluation of structural characterization and component stability showed that cur-cum complex exhibited better anticancer properties with enhanced thermal properties. The cur-cum complex shows pH sensitive sustained release behaviour with higher release at acidic pH and kinetic data of drug release follows the Korsmeyer-Peppas model. The cur-cum complex has ability to block the proliferation of the MCF-7 cell line as revealed by MTT assay which showed increased toxicity of cur-cum complex against these cell lines. The results obtained from western blot analysis demonstrated that the co-administration of cur and cum effectively induced apoptosis in MCF-7 cells. This effect was observed by a considerable upregulation of the Bcl-2/Bax ratio, a decline in mRNA expression of LDHA, level of lactate and LDH activity. The results clearly depict the role of functionalized curdlan as efficient carrier for curcumin delivery with prolonged, sustained release and enhanced bioavailability, thereby improving the overall anticancer activity.
研究领域:
药学
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生物医学工程
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癌症研究
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药物递送系统
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高影响因子
Acta Pharmaceutica Sinica B
·
2021
·
IF 11.614
Yang Zhou,Fan Tong,Weilong Gu,Siqin He,Xiaotong Yang,Jiamei Li,Yue-Dong Gao,Huile Gao
Considering that photodynamic therapy (PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac (Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species (ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A (LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1 α (HIF-1 α ) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo .
研究领域:
癌症治疗
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纳米技术
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药学
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分子生物学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-14
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IF 9.429
Ruan Shuangrong,Yin Weimin,Chang Jiao,Yang Yan,Sun Jiuyuan,Ma Xiaoyi,Liu Ying,Zang Jie,Liu Yiqiong,Li Yongyong,Ren Tianbin,Dong Haiqing
Hypoxia and high accumulation of lactic acid in the tumor microenvironment provide fertile soil for tumor development, maintenance and metastasis. Herein, we developed a calcium peroxide (CaO2)-loaded nanostructure that can play a role of “one stone kill two birds”, i.e., acidic and hypoxic tumor microenvironment can be simultaneously regulated by CaO2 loaded nanostructure. Specifically, CaO2-loaded mesoporous polydopamine nanoparticles modified with sodium hyaluronate (denoted as CaO2@mPDA-SH) can gradually accumulate in a tumor site. CaO2 exposed in acidic microenvironment can succeed in consuming the lactic acid with oxygen generation simultaneously, which could remodel the acid and hypoxia tumor microenvironment. More importantly, the relief of hypoxia could further reduce lactate production from the source by down-regulating the hypoxia inducible factor-1α (HIF-1α), which further down-regulated the glycolysis associated enzymes including glycolysis-related glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). As a result, CaO2@mPDA-SH alone without the employment of other therapeutics can dually regulate the tumor hypoxia and lactic acid metabolism, which efficiently represses tumor progression in promoting immune activation, antitumor metastasis, and anti-angiogenesis.
研究领域:
纳米技术
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肿瘤学
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药学
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生物医学工程
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PubMed
高影响因子
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