bims-prolim Biomed News
on Protein lipidation, metabolism and cancer
Issue of 2025–12–14
twelve papers selected by
Bruna Martins Garcia, CABIMER
  1. Targeting palmitoylation: A novel frontier in cancer biology and immunotherapy.
  2. Protein succinylation in tumors-from biology to clinical therapy.
  3. Targeting Lactylation for Cancer: Mechanisms, Effects, and Therapeutic Prospects.
  4. Lactylation-driven NSUN2-mediated RNA m5C modification promotes perineural invasion in pancreatic cancer.
  5. Lactylation in colorectal cancer: From mechanism to clinical application.
  6. Succinylation heterogeneity in lung adenocarcinoma: from prognostic model to KLK6-driven tumor microenvironment remodeling.
  7. Emerging insights into cell differentiation: the role of N-glycosylation in differentiation-based cancer therapies.
  8. Integrated Genomic and Functional Characterization of Palmitoylation in Clear Cell Renal Cell Carcinoma.
  9. Brusatol inhibits gastric cancer by targeting P4HA2 and supressing glycolysis-driven histone lactylation.
  10. Integrin β3 Orchestrates Hepatic Steatosis via a Novel CD36-Dependent Lipid Uptake Complex.
  11. KAT2A Deficiency Suppresses Lung Cancer Progression by Downregulating MYC Through Decreasing MYC Succinylation.
  12. HDAC5 deficiency induces intrinsic resistance to KRAS inhibition by disrupting c-Myc acetylation-ubiquitination homeostasis.
  1. Biochim Biophys Acta Rev Cancer. 2025 Dec 07. pii: S0304-419X(25)00251-3. [Epub ahead of print] 189509
    Targeting palmitoylation: A novel frontier in cancer biology and immunotherapy.
    Ye Yang, Enqi Zhang, Xuanli Mao, Guohong Liu, Yunbao Pan.
      Protein palmitoylation, a dynamic post-translational modification involving the reversible attachment of palmitic acid to cysteine residues, has emerged as a pivotal regulator of tumor biology. This review synthesizes the latest insights into palmitoylation's contributions to cancer, emphasizing its roles in metabolic reprogramming, oncogenic signaling, immune modulation, and therapeutic responsiveness. The ZDHHC family of palmitoyltransferases, in concert with depalmitoylases, coordinates intricate regulatory networks that govern protein localization, stability, and interactions essential for tumor proliferation, invasion, and immune evasion. Driven by dysregulated lipid metabolism, aberrant palmitoylation modulates key pathways such as AKT-mTOR and Wnt/β-catenin, while also stabilizing immune checkpoints like PD-L1 and TIM-3 to sculpt an immunosuppressive tumor microenvironment. Advances in multi-omics integration and detection technologies, including high-resolution mass spectrometry and imaging modalities, have deepened our mechanistic understanding of these processes. Preclinical evidence underscores the promise of small-molecule inhibitors like 2-bromopalmitate and TVB-3166, which disrupt palmitoylation to inhibit tumor growth and potentiate immunotherapy. Nonetheless, hurdles in selectivity, toxicity, and resistance demand further optimization for clinical translation. Future research should focus on unraveling palmitoylation's interplay with immune dynamics and advancing biomarker-guided, personalized therapies to elevate cancer outcomes.
    Keywords:  Immune checkpoints; Palmitoylation; Targeted therapy; Tumor metabolism; Tumor microenvironment; ZDHHC
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189509
  2. Int J Biol Macromol. 2025 Dec 06. pii: S0141-8130(25)10046-9. [Epub ahead of print] 149489
    Protein succinylation in tumors-from biology to clinical therapy.
    Huiling Li, Huijuan Zhang, Jing Zhu, Yu Tang, Jing An.
      Lysine succinylation is a recently identified post-translational modification (PTM) characterized by the transfer of a succinyl group (-CO-CH2-CH2-CO2H) to lysine residues, primarily mediated by succinyl-CoA. This modification plays a critical role in maintaining protein stability and function, and is involved in diverse biological processes, including energy metabolism, substrate transport, and signal transduction. Accumulating evidence indicates that lysine succinylation contributes to tumorigenesis and cancer progression, with both enzymatic and non-enzymatic mechanisms playing regulatory roles. This review summarizes recent advances in succinylation research within the context of tumor metabolism, the tumor immune microenvironment, and its interplay with other epigenetic modifications. Furthermore, we highlight current developments in anti-tumor therapeutics and succinylation inhibitors, aiming to provide novel insights into protein post-translational modifications and to support the identification of potential drug targets for clinical applications.
    Keywords:  Cell metabolism; Epigenetic regulation; Immune microenvironment; Post-translational modification; Succinylation; Therapy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.149489
  3. Int J Mol Sci. 2025 Nov 21. pii: 11278. [Epub ahead of print]26(23):
    Targeting Lactylation for Cancer: Mechanisms, Effects, and Therapeutic Prospects.
    Dong Chang, Daolong Li, Yuxi Sun, Jiekang Shi, Shengping Zhang, Chuangui Wang.
      Recent studies reveal that lysine lactylation plays a pivotal and multifaceted role in tumor progression. Here, we provide a systematic overview of the mechanisms underlying lactylation, highlighting its regulation of tumor metabolic reprogramming and immune microenvironment remodeling. We further summarize how lactylation drives malignancy across diverse cancer types and discuss emerging strategies to therapeutically target lactylation in cancer. By integrating current findings, this review offers a comprehensive framework for understanding lactylation in tumor biology and identifies key gaps for future investigation, thereby providing a valuable reference for both basic research and therapeutic development.
    Keywords:  immune microenvironment; lactate; lactylation; metabolic; tumor
    DOI:  https://doi.org/10.3390/ijms262311278
  4. Theranostics. 2026 ;16(4): 1782-1803
    Lactylation-driven NSUN2-mediated RNA m5C modification promotes perineural invasion in pancreatic cancer.
    Tianhao Huang, Chonghui Hu, Huimou Chen, Honghui Jiang, Tingting Li, Qing Tian, Rihua He, Yuan Yuan, Yong Jiang, Yu Zhou, Qing Lin, Zhihua Li, Mingming Xiao, Xuebiao Wei, Rufu Chen, Shangyou Zheng.
      Background: Perineural invasion (PNI) is a key biological feature underpinning the high malignancy and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Lysine lactylation (Kla), a metabolite-stress-induced post-translational modification, plays crucial regulatory roles in diverse biological processes. The RNA methyltransferase NSUN2 is essential for cancer invasion and metastasis. However, the mechanisms by which NSUN2 contributes to lactylation-driven PNI in PDAC remain to be elucidated. Methods: We assessed tumor lactate / pan-lactylation, NSUN2 lactylation, and PNI in human PDAC cohorts with survival follow-up. Functional studies used PDAC cell lines for migration/invasion assays, dorsal-root-ganglion (DRG) co-culture, and neurite-outgrowth assays under lactate or enzymatic perturbations. Mechanistic interrogation combined NSUN2 knockout, CRISPR knock-in mutants at K692 (K692R/E), co-immunoprecipitation, RIP-seq, MeRIP-qPCR, and actinomycin-D chase to test mRNA binding, m5C modification, and stability of CDCP1/STC1. In vivo validation employed a sciatic nerve invasion model and a KPC genetically engineered mouse model to assess tumor-nerve infiltration and disease progression. Results: Lactylated NSUN2 is markedly upregulated in mice and human PDAC with more severe PNI, and is significantly associated with poorer prognosis. Functionally, inhibiting lactylation or blocking NSUN2 markedly attenuated tumor-nerve interactions and neural invasion. Mechanistically, lactate accumulation leads to the lactylation of NSUN2 at lysine 692 (K692), subsequently inhibiting its ubiquitination and degradation. lactylation of NSUN2 mediated m5C modification on CDCP1 and STC1 mRNA, enhanced their mRNA stability. Conclusions: This study identifies lactate-driven NSUN2 K692 lactylation as a key driver of perineural invasion in PDAC. We define a lactate-NSUN2-m5C-CDCP1/STC1 axis that links metabolic stress-induced lysine lactylation to mRNA methylation-dependent stabilization of pro-invasive transcripts, highlighting actionable therapeutic targets to restrain neural invasion and improve patient outcomes.
    Keywords:  NSUN2; lactylation modification; m5C; pancreatic ductal adenocarcinoma (PDAC); perineural invasion
    DOI:  https://doi.org/10.7150/thno.122294
  5. Biochem Pharmacol. 2025 Dec 06. pii: S0006-2952(25)00886-X. [Epub ahead of print]244 117621
    Lactylation in colorectal cancer: From mechanism to clinical application.
    Peng Chen, Yu-Hong Gao, Shu-Xian Xie, Yun Lei.
      Lactylation is an emerging epigenetic modification that dynamically modifies lysine residues of histones and non-histones through lactate, thereby regulating protein function and gene expression. In recent years, the role of lactylation in cancer has garnered significant attention, as it plays a key role in metabolic reprogramming, immune evasion, tumor metastasis, and drug resistance. Colorectal cancer (CRC), one of the most common malignant tumors globally, is closely associated with lactylation. This review systematically summarizes the molecular mechanisms of lactylation and its biological functions in the occurrence and development of CRC. Given the limited current research on lactylation and CRC, we also summarize the role of lactylation in cancer and the directions and progress of targeted lactylation therapy for cancer.
    Keywords:  Colorectal cancer; Drug resistance; Epigenetic; Lactylation; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.bcp.2025.117621
  6. Front Immunol. 2025 ;16 1718994
    Succinylation heterogeneity in lung adenocarcinoma: from prognostic model to KLK6-driven tumor microenvironment remodeling.
    Jichang Liu, Xuehan Zhu, Chenlong Zha, Jiaqi Ding, Chuanpeng Zhang, Yizhe Wang, Tao Yan, Hui Kong, Yong Liu, Jingyu Chen.
       Background: Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality. Protein succinylation, a key post-translational modification, is implicated in tumor progression. However, its comprehensive landscape and clinical significance in LUAD remain largely unexplored.
    Methods: We integrated multi-omics data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts. A set of core succinylation-related genes was identified through differential expression and univariable Cox regression analyses. Molecular subtypes based on succinylation were determined by principal component analysis (PCA). A succinylation prognostic model was constructed via least absolute shrinkage and selection operator (LASSO) and multivariable Cox regression. The differences of tumor microenvironment (TME), tumor mutation burden and drug sensitivity in different risk groups were further explored. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics revealed effects of succinylation on TME. High-dimensional weighted gene co-expression networks analysis (hdWGCNA) was used to identify potential succinylation-related therapeutic targets. The function of therapeutic targets was further validated through scRNA-seq, spatial transcriptomics, and in vitro experiments.
    Results: We identified 31 core succinylation-related genes and defined three molecular subtypes with distinct prognostic and TME characteristics. A robust 7-gene succinylation-based prognostic signature was developed and validated across 7 independent GEO cohorts, effectively stratifying patients into high- and low-risk groups with significant differences in survival, demonstrating high predictive accuracy, consistency, and clinical utility. The low-risk group exhibited an immunoreactive TME with enhanced immune cell infiltration and superior response to immunotherapy. scRNA-seq and spatial transcriptomics revealed enhanced succinylation in LUAD. Kallikrein-related peptidase 6 (KLK6) was identified as a potential therapeutic target. KLK6 was significantly upregulated in LUAD, correlated with poor prognosis and therapy resistance. KLK6 promoted global succinylation, proliferation, migration, and invasion of LUAD cells in vitro. Mechanistically, KLK6-positive tumor cells might foster an immunosuppressive TME by driving fibroblast-to-myofibroblast differentiation, enhancing extracellular matrix (ECM) deposition, and inhibiting CD8+ T cell infiltration.
    Conclusion: Our study delineates the succinylation landscape in LUAD, establishes a novel prognostic model for risk stratification and immunotherapy prediction. Meanwhile, we identified KLK6 as a potential promoter of tumor progression and immunosuppression. Targeting the succinylation pathway, particularly KLK6, may represent a promising therapeutic strategy for LUAD.
    Keywords:  KLK6; immunotherapy; lung adenocarcinoma; prognosis; succinylation
    DOI:  https://doi.org/10.3389/fimmu.2025.1718994
  7. Carbohydr Res. 2025 Dec 03. pii: S0008-6215(25)00413-6. [Epub ahead of print]560 109787
    Emerging insights into cell differentiation: the role of N-glycosylation in differentiation-based cancer therapies.
    Tiangui Wu, Pengfei Ye, Junjie Yang, Yuhan Sun.
      N-glycosylation is a dynamic post-translational modification that critically regulates cancer cell differentiation through modulating receptor signaling, cell adhesion, and plasticity. Aberrant N-glycosylation promotes dedifferentiation, drives EMT, and confers therapy resistance across malignancies. This review summarizes the role of N-glycosylation in determining lineage commitment and altering responses to differentiation therapies. Targeting the N-glycosylation apparatus can reprogram tumor cells toward differentiated phenotypes, potentiating the effects of agents such as ATRA and NaBu. Evidence from leukemia and solid tumors reveals the therapeutic potential of disrupting glycan-dependent cell fate decisions. Deciphering these "glycan codes" provides a framework for integrating glycosylation modifiers into precision differentiation therapies, offering novel strategies to overcome treatment resistance.
    Keywords:  Cell differentiation; Differentiation-inducing therapy; Epithelial-mesenchymal transition (EMT); N-Glycosylation; N-glycan
    DOI:  https://doi.org/10.1016/j.carres.2025.109787
  8. Hum Mutat. 2025 ;2025 4647115
    Integrated Genomic and Functional Characterization of Palmitoylation in Clear Cell Renal Cell Carcinoma.
    Dong Zhang, Ke Zhang, Minghao Deng, Jiakang Ma, Jian Zhu, Shuijie Shen, Jianjun Xie, Chao Chen.
       Background: Clear cell renal cell carcinoma (ccRCC) is a highly aggressive cancer with a poor prognosis. Palmitoylation, a posttranslational modification, plays a key role in regulating cancer progression and immune responses. However, its influence on ccRCC prognosis and immune therapy efficacy remains underexplored.
    Methods: Multiple publicly available ccRCC datasets were integrated and harmonized through batch effect correction. A prognostic model based on palmitoylation-related genes was constructed using a combination of 101 machine learning algorithms. Single-cell RNA sequencing was employed to analyze cellular heterogeneity within the tumor microenvironment. Genomic profiling, including tumor mutational burden (TMB), copy number variation (CNV), and tumor stemness, was conducted to identify genomic differences between the high- and low-risk groups. Immune infiltration levels were assessed using various algorithms to compare immune profiles across patient subgroups, while immune therapy responses were predicted using multiple prediction models. Experimental validation of ZDHHC18, a key gene in the prognostic model, was performed in ccRCC cell lines (786-O and Caki-1) to evaluate its impact on cell proliferation, migration, and invasion.
    Results: The palmitoylation-related prognostic model effectively stratified ccRCC patients into the high- and low-risk groups, with distinct differences in survival outcomes. Genomic analysis demonstrated higher TMB and CNV alterations in the high-risk group. Immune response predictions indicated that low-risk patients were more likely to benefit from immunotherapy. Additionally, ZDHHC18 was significantly upregulated in ccRCC tumor tissues, and its knockdown notably inhibited cell proliferation, migration, and invasion.
    Conclusion: Palmitoylation-related genes, particularly ZDHHC18, serve as promising prognostic biomarkers and predictive indicators for immune therapy in ccRCC. These findings offer new insights into ccRCC biology and highlight potential therapeutic targets for improving patient outcomes.
    Keywords:  ZDHHC18; clear cell renal cell carcinoma; immunotherapy; machine learning; palmitoylation; single-cell RNA sequencing
    DOI:  https://doi.org/10.1155/humu/4647115
  9. Phytomedicine. 2025 Dec 05. pii: S0944-7113(25)01213-9. [Epub ahead of print]150 157585
    Brusatol inhibits gastric cancer by targeting P4HA2 and supressing glycolysis-driven histone lactylation.
    Kaiyuan Zhang, Xiaochen Ni, Chuhang Wang, Jianing Guo, Wei Fan, Tao Jiang, Guangji Zhang.
       BACKGROUND: Brusatol (BRU) is a bioactive derived from Brucea javanica. It has demonstrated anti-tumor effects in gastric cancer (GC). However, its role in regulating metabolic-epigenetic cross-talk remains poorly understood.
    PURPOSE: This study aimed to elucidate how BRU inhibits GC progression by modulating metabolic reprogramming and histone lactylation.
    METHODS: We treated GC cell lines (AGS and MKN45) and xenograft models with BRU. Our methodology combined multi-omics analysis, molecular docking, CETSA, metabolic assays, and CUT&Tag sequencing. We used functional validation through prolyl-4-hydroxylase subunit alpha-2 (P4HA2) overexpression and lactate rescue experiments.
    RESULTS: BRU selectively inhibited GC proliferation with minimal toxicity to normal gastric cells. Using multi-omics approaches, we found that BRU treatment markedly suppressed glycolysis, as evidenced by the downregulation of key enzymes. Integrated omics identified P4HA2 as a key target, which BRU bound directly and promoted its lysosomal degradation. P4HA2 suppression downregulated glycolytic enzymes, reducing lactate production. Consequently, BRU decreased histone H3K9lac/H3K18lac modifications by inhibiting the lactylation "writer" HBO1. CUT&Tag results showed that BRU lowered H3K18lac occupancy at gene promoters. This lactylation decline suppressed transcription of the mitotic regulator TTK. In vivo, BRU suppressed tumor growth and reduced Ki-67, PCNA, LDHA, Pan-Kla, H3K9lac, and H3K18lac levels.
    CONCLUSION: BRU inhibites GC progression by targeting P4HA2, disrupting glycolysis-histone lactylation signaling, and downregulating TTK. This metabolic-epigenetic mechanism positions BRU as a promising natural therapeutic for GC.
    Keywords:  Brusatol; Gastric cancer; Glycolysis; Histone lactylation; P4HA2
    DOI:  https://doi.org/10.1016/j.phymed.2025.157585
  10. Adv Sci (Weinh). 2025 Dec 08. e17455
    Integrin β3 Orchestrates Hepatic Steatosis via a Novel CD36-Dependent Lipid Uptake Complex.
    Ying Zhang, Lei Dai, Zhongquan Cui, Ye Zhou, Wenyuan Dong, Hongcheng Jiang, Mengwen Wang, Xiaodan Zhong, Wei Dong, Zhang Yue, Thati Madhusudhan, Hongjie Wang, Xiong Zhong Ruan, Hesong Zeng.
      In metabolic dysfunction-related steatohepatitis (MASH), ITGB3 promotes hepatic fibrosis via activating hepatic stellate cells, but whether it directly regulates hepatic lipid metabolism through membrane-scaffolding function and the underlying mechanisms remain unclear. Transcriptomic analyses of human and murine models of MASH revealed consistent upregulation of ITGB3 in hepatocytes. In mice, the hepatocyte-specific overexpression of ITGB3 exacerbates diet-induced obesity, insulin resistance, steatosis, and fibrosis, the deletion of ITGB3 alleviates these phenotypes. Additionally, the overexpression of DHHC5 reversed the hallmarks of MASH in ITGB3-deficient mice, confirming the central role of DHHC5 in this process. Mechanistically, ITGB3 is a novel "accelerator" that directly increases CD36-mediated fatty acid uptake by recruiting LYN, then modulating LYN protein stability, and triggering LYN proteasomal degradation. This degradation relieves LYN-mediated inhibition of DHHC5 and promotes ITGB3/DHHC5/CD36 complex formation, thereby enhancing DHHC5-dependent CD36 palmitoylation and subsequent CD36-mediated fatty acid uptake. Pharmacologic inhibition of ITGB3 using cyclic-RGDfk peptide improved serum lipid profiles and hepatic steatosis. This study uncovers a previously unrecognized mechanism by which ITGB3 acts as a driver of hepatic steatosis of hepatic steatosis. Targeted intervention against ITGB3 to modulate CD36-mediated lipid uptake may represent a novel therapeutic strategy for the treatment of MASH.
    Keywords:  CD36; MASH; integrin β3; lipid uptake; metabolic stress
    DOI:  https://doi.org/10.1002/advs.202517455
  11. Cancer Sci. 2025 Dec 09.
    KAT2A Deficiency Suppresses Lung Cancer Progression by Downregulating MYC Through Decreasing MYC Succinylation.
    Junping Li, Feng Zhao, Zhongchao Wang, Shaojun Yang, Zhichao Lu, Xiaoyan Li, Jincheng Song, Zhaoxia Dai.
      Succinylation has been shown to promote lung cancer development, but its mechanism remains incompletely understood. KAT2A, a succinyltransferase, acts as an oncogene in multiple cancers, but its role in mediating lung cancer progression is unclear. This study aimed to investigate the mechanism by which KAT2A regulates lung cancer progression via succinylation. KAT2A expression was analyzed using UALCAN, GEPIA, and Kaplan-Meier Plotter databases, and validated in lung cancer cell lines and patient-derived tissues. Quantitative real-time PCR, Cell Counting Kit-8 (CCK-8), EdU staining, and flow cytometry were performed to assess KAT2A's role in lung cancer cell proliferation and apoptosis. KAT2A's target proteins were predicted using LinkedOmics and STRING databases. Additionally, in vivo xenograft models were established to evaluate the effect of KAT2A knockdown on tumor growth. Results indicated that KAT2A expression was significantly elevated in lung cancer cells and tissues and was associated with poor prognosis. KAT2A knockdown inhibited proliferation and promoted apoptosis in lung cancer cells, whereas MYC overexpression reversed these effects. Mechanistically, KAT2A knockdown downregulated MYC by reducing succinylation at K370 and K386 residues. Mutation of these sites abrogated the proliferative effect of MYC overexpression and restored apoptotic activity. Furthermore, in vivo experiments demonstrated that KAT2A knockdown inhibited tumor growth and reduced MYC succinylation. Our findings demonstrate that KAT2A functions as an oncogene in lung cancer by enhancing MYC succinylation. This study identifies KAT2A as a promising therapeutic target for lung cancer.
    Keywords:  KAT2A; MYC; lung cancer; succinylation
    DOI:  https://doi.org/10.1111/cas.70286
  12. J Clin Invest. 2025 Dec 11. pii: e195814. [Epub ahead of print]
    HDAC5 deficiency induces intrinsic resistance to KRAS inhibition by disrupting c-Myc acetylation-ubiquitination homeostasis.
    Taoyu Chen, Haixin Yu, Keshan Wang, Gengdu Qin, Yuhan Zhao, Xueyi Liang, Yuxuan Li, Tianhao Zou, Jiaying Liu, Jingyuan Zhao, Zhiqiang Liu, Ruozheng Wei, Bo Wang, Shanmiao Gou, Tao Yin, Heshui Wu, Xin Jin, Yingke Zhou.
      KRAS mutations serve as key oncogenic drivers in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Despite the advancement of KRAS inhibitors like MRTX1133 for PDAC treatment, intrinsic and acquired resistance remain major barriers to their clinical efficacy. This study underscored the role of histone deacetylase 5 (HDAC5) loss in mediating intrinsic resistance to KRASG12D inhibitors. Mechanistically, HDAC5 promoted c-Myc degradation by deacetylating K148, thereby facilitating NEDD4-mediated ubiquitination at this site. The loss of HDAC5 resulted in hyperacetylation of c-Myc at K148, impeding the ubiquitination and subsequent degradation process of c-Myc following deacetylation. Consequently, c-Myc stability and transcriptional activity were sustained even under KRAS-MEK-ERK pathway inhibition, reinforcing MAPK signaling and promoting cell survival despite KRAS suppression. Our data further demonstrated that pharmacological or genetic inhibition of c-Myc effectively reversed the resistance phenotype mediated by HDAC5 loss, suggesting a therapeutic strategy centered on "KRAS-MYC dual-node blockade." Furthermore, the expression levels of HDAC5 and the acetylation status of c-Myc may serve as potential biomarkers for predicting the therapeutic response to MRTX1133. These findings provide insights into overcoming resistance to KRASG12D inhibitors and offer potential biomarkers and combinatorial therapeutic strategies for precision treatment of PDAC.
    Keywords:  Cancer; Cell biology; Drug therapy; Epigenetics; Oncology
    DOI:  https://doi.org/10.1172/JCI195814
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