bims-prolim 2025-05-25 papers

bims-prolim

Biomed News

on Protein lipidation, metabolism and cancer

Issue of 2025–05–25
fourteen papers selected by
Bruna Martins Garcia, CABIMER

Acyl post-translational modification of proteins by metabolites in cancer cells.
[Research Progress and Applications of ZDHHC-mediated Protein Palmitoylation  in the Development and Immune Escape of Non-small Cell Lung Cancer].
Proteomics and succinylation modification characterization in clear cell renal cell carcinoma.
NCAPD3 contributes to lung cancer progression through modulated lactate-induced histone lactylation and MEK/ERK/LDHA axis.
Personalized treatment decision-making using a machine learning-derived lactylation signature for breast cancer prognosis.
Glycosylation in cancer: mechanisms, diagnostic markers, and therapeutic applications.
Lactylation-boosted polycomb repression of KLF4 elicits glycolysis in retinoblastoma: A positive feedback circuit between histone modifications.
Lactate-associated gene MCU promotes the proliferation, migration, and invasion of pancreatic ductal adenocarcinoma.
GCNT3-mediated glycosylation in cancer biology: Implications for tumorigenesis, metastasis, and therapeutic targeting.
Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysis.
AIE-Active Probe for Unveiling the Role of Protein Sulfenylation In Vivo: Specific Imaging and Therapeutic Insights.
Selenoprotein K-dependent MyD88 palmitoylation promotes hepatic metaflammation in high-fat diet fed mice.
S-palmitoylation coordinates the trafficking of ATG9A to mediate autophagy initiation.
OGT-mediated O-GlcNAc of PINK1 promotes the progression of obesity-related hypertension via regulating mitophagy.

Cell Death Discov. 2025 May 21. 11(1): 247

Acyl post-translational modification of proteins by metabolites in cancer cells.

Xudong Wang, Yining Guo, Yutian Fu, Chen Zhang, Weiwu Chen, Xinyu Tang, Yanlan Yu, Yicheng Chen, Guoqing Ding, Jie Zhang.

The relationship between metabolism and cancer is a major focus of current research, with an increasing number of studies highlighting the significant role of various metabolites in tumor cells, such as lactate, acetic acid, lysine, serine, tryptophan, palmitic acid, succinate, etc. These metabolites are involved in numerous biological processes within tumor cells, including transcription, translation, post-translational modification (PTM) of proteins, cell cycle regulation, and metabolism, thereby modulating tumor proliferation, migration, and drug resistance. Metabolite-mediated PTMs of proteins undoubtedly play a vital role in tumor cells, affecting both histones and non-histone proteins, covering modifications such as lactylation, crotonylation, acetylation, palmitoylation, and succinylation. Therefore, this review aims to elaborate on the abnormal levels of some major metabolites, related metabolic pathways, and the latest protein acyl PTMs they mediate in tumor cells, providing new insights for diagnosis and therapy in the field of oncology.

DOI: https://doi.org/10.1038/s41420-025-02535-4
Zhongguo Fei Ai Za Zhi. 2025 Apr 20. 28(4): 319-324

[Research Progress and Applications of ZDHHC-mediated Protein Palmitoylation  in the Development and Immune Escape of Non-small Cell Lung Cancer].

Wangcheng Chen, Lili Pang, Yuemei Lan, Yanhong Shi, Bingbing Wen, Baihong Zhang.

  Non-small cell lung cancer (NSCLC), a leading cause of cancer-related deaths worldwide, remains a significant clinical challenge despite advances in immune checkpoint inhibitors therapy, with drug resistance persisting as a major obstacle. Palmitoylation, a critical post-translational modification (PTM) primarily catalyzed by palmitoyltransferases of the zinc finger DHHC-type (ZDHHC), has recently demonstrated important implications in NSCLC. This review aims to elucidate the mechanisms and clinical potential of ZDHHC-mediated protein palmitoylation in NSCLC progression and immune escape. .

Keywords:  Immune escape; Lung neoplasms; PD-L1; Protein palmitoylation; ZDHHC enzymes

DOI:  https://doi.org/10.3779/j.issn.1009-3419.2025.102.15
Discov Oncol. 2025 May 20. 16(1): 835

Proteomics and succinylation modification characterization in clear cell renal cell carcinoma.

Dong Yue, Miao Zheng.

  Clear cell renal cell carcinoma (ccRCC) represents the most lethal form of kidney cancer, with a significant number of patients experiencing tumor progression. Succinylation modification is a novel post-translational modification (PTM) that refers to modifying a protein with a succinyl group, which most frequently happens to lysine residues. Recent studies have revealed that abnormal succinylation, altered protein activity, dysfunctional roles in energy metabolism, and subsequent epigenetic modifications are linked to the onset and progression of conditions like inflammation, cancer, and other diseases. No studies have offered a comprehensive analysis of succinylation modification in ccRCC or clarified the mechanisms by which this modification operates within disease progression. In this study, we applied quantitative proteomics and succinylation modification omics to extensively examine the global proteome and succinylation modification changes in ccRCC tissues. Using high-throughput liquid chromatography-mass spectrometry, we identified 4801 lysine succinylation modification sites across 1274 proteins in ccRCC and adjacent non-cancerous tissues. Additionally, 434 succinylation sites within 328 proteins displayed significant differential modification in ccRCC (fold change (FC) > 1.5 or p < 0.05). Notably, the succinylated proteins were primarily associated with energy metabolism pathways, including fatty acid elongation, glyoxylate and dicarboxylate metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation, and were predominantly located within the mitochondria. This study is the first to present a global proteomic profile and a detailed succinylation modification landscape in ccRCC. These findings introduce new potential approaches for treating ccRCC by reversing abnormal succinylation modifications.

Keywords:  Clear cell renal cell carcinoma; Energy metabolism; Mitochondria; Succinylation modification

DOI:  https://doi.org/10.1007/s12672-025-02737-3
Cancer Cell Int. 2025 May 23. 25(1): 189

NCAPD3 contributes to lung cancer progression through modulated lactate-induced histone lactylation and MEK/ERK/LDHA axis.

Zhibo Chang.

  Lung cancer (LC) is one of the most common malignant tumors globally. Non-SMC condensin II complex subunit D3 (NCAPD3) has been involved in the progression of many kinds of tumors. However, the effects of NCAPD3 in LC remain unclear. NCAPD3 expression was investigated by the Ualcan database and using Western blot. The effect of NCAPD3 on prognosis was explored via the Kaplan-Meier plotter database. Cell viability, colony formation, apoptosis, and Transwell assays, and in vivo tumorigenesis were performed to reveal the biological roles of NCAPD3. Glycolysis was assessed via measurement of glucose consumption, extracellular acidification rate (ECAR), lactate production, and ATP levels. The deeper mechanisms of NCAPD3 were investigated by Western blot and rescue experiments. Upregulation of NCAPD3 levels in LC tissues was found in Ualcan and significantly associated with poor prognosis. The expression of NCAPD3 was up-regulated in LC cell lines compared to BEAS-2B cells. Knockdown and overexpression experiments suggested that proliferation, apoptosis, migration, invasion, and glycolysis were regulated by NCAPD3 via the MEK/ERK/LDHA pathway. Additionally, NCAPD3 knockdown inhibited tumor growth in vivo. Mechanistically, NCAPD3 overexpression-mediated activation of the MEK/ERK/LDHA pathway and proliferation, Glucose uptake, and glycolysis were attenuated by MEK inhibitor U0126. Also, histone lactylation helps in tumorigenesis by promoting NCAPD3 expression. Taken together, our results revealed that histone lactylation of NCAPD3 promoted proliferation, migration, invasion, and glycolysis through modulating the MEK/ERK/LDHA signaling pathway in LC, which highlights a novel understanding of NCAPD3 in LC.

Keywords:  Glycolysis; Histone lactylation; Lung cancer; NCAPD3

DOI:  https://doi.org/10.1186/s12935-025-03814-x
Front Immunol. 2025 ;16 1540018

Personalized treatment decision-making using a machine learning-derived lactylation signature for breast cancer prognosis.

Simin Min, Xiaonan Zhang, Yuling Liu, Weiqiang Wang, Jingwen Guan, Yuyan Chen, Meng Sun, Ziheng Wang, Tao Wang.

   Background: Breast cancer is a heterogeneous malignancy with complex molecular characteristics, making accurate prognostication and treatment stratification particularly challenging. Emerging evidence suggests that lactylation, a novel post-translational modification, plays a crucial role in tumor progression and immune modulation.
Methods: To address breast cancer heterogeneity, we developed a machine learning-derived lactylation signature (MLLS) using lactylation-related genes selected through random survival forest (RSF) and univariate Cox regression analyses. A total of 108 algorithmic combinations were applied across multiple datasets to construct and validate the model. Immune microenvironment characteristics were analyzed using multiple immune infiltration algorithms. Computational drug-repurposing analyses were conducted to identify potential therapeutic agents for high-risk patients.
Results: The MLLS effectively stratified patients into low- and high-risk groups with significantly different prognoses. The model demonstrated robust predictive power across multiple cohorts. Immune infiltration analysis revealed that the low-risk group exhibited higher levels of immune checkpoints (e.g., PD-1, PD-L1) and greater infiltration of B cells, CD4+ T cells, and CD8+ T cells, suggesting better responsiveness to immunotherapy. In contrast, the high-risk group showed immune suppression features associated with poor prognosis. Methotrexate was computationally predicted as a potential therapeutic candidate for high-risk patients, although experimental validation remains necessary.
Conclusion: The MLLS represents a promising prognostic biomarker and may support personalized treatment strategies in breast cancer, particularly for identifying candidates who may benefit from immunotherapy.

Keywords:  breast cancer prognosis; immune microenvironment; immunotherapy; lactylation; machine learning

DOI:  https://doi.org/10.3389/fimmu.2025.1540018
Mol Cell Biochem. 2025 May 19.

Glycosylation in cancer: mechanisms, diagnostic markers, and therapeutic applications.

Zahraa Qusairy, Miran Rada.

  Glycosylation, a key post-translational modification, plays a pivotal role in cancer progression by influencing critical processes such as protein folding, immune modulation, and intercellular signaling. Altered glycosylation patterns are increasingly recognized as fundamental drivers of tumorigenesis, contributing to key cancer hallmarks like enhanced tumor migration, metastasis, and immune evasion. These aberrant glycosylation signatures not only offer insights into cancer biology but also serve as valuable diagnostic markers and potential therapeutic targets across a range of malignancies. This review explores the mechanisms underlying glycosylation alterations in cancer. We discuss the molecular basis of these changes, including genetic mutations, epigenetic regulation, and oncogene-driven shifts in glycosylation pathways. Additionally, we highlight recent advancements in glycomics research, with a focus on how these alterations influence tumor progression, angiogenesis, and the tumor microenvironment. Furthermore, the review considers the clinical implications of glycosylation changes, including their role in resistance to anti-cancer therapies and their potential as biomarkers for personalized treatment strategies. By bridging fundamental glycosylation research with clinical applications, this review underscores the promise of glycosylation as both a diagnostic tool and a therapeutic target in oncology, offering new avenues for improved patient stratification and precision medicine.

Keywords:  Aberrant glycosylation; Cancer biomarkers; Fucosylation; Glycomics; Glycosylation; Sialylation; Targeted therapy; Truncation

DOI:  https://doi.org/10.1007/s11010-025-05303-1
Cancer Lett. 2025 May 16. pii: S0304-3835(25)00371-4. [Epub ahead of print]625 217804

Lactylation-boosted polycomb repression of KLF4 elicits glycolysis in retinoblastoma: A positive feedback circuit between histone modifications.

Ludi Yang, Sipeng Zuo, Ruobing Jia, Xiang Gu, Qili Liao, Yu Hua, Shengfang Ge, Mengjia He, Jiayan Fan, Xuemei Tong, Tifei Yuan, Renbing Jia, Xianqun Fan, Peiwei Chai, Xuyang Wen.

  The perturbation of histone modification homeostasis is a hallmark of oncogene activation and tumor suppressor gene silencing. Howbeit, the intricate interplay among diverse histone modifications in the context of tumorigenesis is not fully understood. Herein, we unveil a positive feedback mechanism involving lactylation and methylation of histones, which is instrumental in the oncogenic progression of retinoblastoma. First, we pinpointed that the selective upregulation of SUZ12 leads to the upregulation of H3K27me3 modification in retinoblastoma, which is attributed to heightened levels of histone lactylation. Notably, the targeted suppression of SUZ12 has demonstrated significant therapeutic benefits in both in vitro and in vivo models of retinoblastoma. Furthermore, multi-omics analysis has identified Krüppel-like factor 4 (KLF4) as a key downstream effector of SUZ12. Mechanistically, SUZ12 is implicated in the enhancement of the H3K27me3 mark on the KLF4 promoter, thereby repressing its transcription. Intriguingly, the downregulation of KLF4 is associated with an upregulation of glycolysis and a concomitant accumulation of the onco-metabolite lactate, which in turn augments histone lactylation. In conclusion, we provide novel insights into the intricate interplay between lactylation and methylation of histones, shedding light on the epigenetic-metabolic reprogramming that underlies oncogene activation and tumor suppressor gene inactivation in cancer.

Keywords:  Glycolysis; H3K27me3; Histone lactylation; Oncogene; SUZ12

DOI:  https://doi.org/10.1016/j.canlet.2025.217804
BMC Cancer. 2025 May 21. 25(1): 913

Lactate-associated gene MCU promotes the proliferation, migration, and invasion of pancreatic ductal adenocarcinoma.

Yuhang Chen, Fenglin Zhang, Suoyi Dai, Jiangang Zhao, Wenxun Cai, Ke Zhang, Xinghe Liao, Lianyu Chen.

   BACKGROUND: The metabolism of lactate and lactylation of proteins are believed to influence tumor development through their effects on the tumor microenvironment and immune escape mechanisms. Nevertheless, its significance in pancreatic ductal adenocarcinoma (PDAC) has yet to be fully understood. This investigation sought to assess the predictive value and treatment implications of lactate-related genes (LRGs) in PDAC.
METHODS: We analyzed PDAC data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), identifying LRGs. Using weighted gene co-expression network analysis (WGCNA) and consensus clustering, we delineated lactate subtypes and extracted differentially expressed genes. Functional enrichment and gene set enrichment analysis (GSEA) analyses were conducted to explore pathways. A lactate-linked risk signature was constructed using Lasso-Cox regression, and its prognostic value was validated. In vitro experiments were executed to examine the function of MCU in PDAC cells. In vitro experiments were conducted to detect the malignant potential of MCU in PDAC cells and its effect on lactic acid metabolism.
RESULTS: Two lactate subtypes were identified, with distinct gene expression profiles and clinical outcomes. The risk signature, comprising four LRGs, predicted survival with significant accuracy. In vitro, MCU knockdown reduced cell proliferation, migration, invasion, and stemness, confirming its role in PDAC malignancy. At the same time, it can also inhibit lactate production and glycolysis processes.
CONCLUSION: Our investigation underscores the importance of LRGs in PDAC, providing a novel prognostic signature and therapeutic target.

Keywords:  Lactate; MCU; Pancreatic adenocarcinoma; Prognosis; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12885-025-14319-1
Int J Biol Macromol. 2025 May 20. pii: S0141-8130(25)04979-7. [Epub ahead of print] 144427

GCNT3-mediated glycosylation in cancer biology: Implications for tumorigenesis, metastasis, and therapeutic targeting.

Lin Zhong, Bhagyalakshmi Purushothaman, Qiang Tu, Seenivasan Boopathi, Youming Zhang.

  Glycosylation is a fundamental post-translational modification that plays a pivotal role in cancer progression, influencing cell adhesion, immune evasion, metastasis, and drug resistance. Among glycosyltransferases, Core 2 β-1,6-N-acetylglucosaminyltransferase 3 (GCNT3) has emerged as a key regulator of tumor behavior, with its effects varying across different cancers. While elevated GCNT3 expression is associated with better prognosis and chemotherapy response in ovarian cancer, it correlates with poor survival, tumor invasiveness, and immune suppression in pancreatic and lung cancers. This dual nature underscores the complexity of GCNT3's role in cancer biology. As a biomarker, GCNT3 has shown potential for prognostic and therapeutic applications, particularly in colorectal and ovarian cancers. Targeting GCNT3 therapeutically presents challenges due to its role in normal physiological glycosylation, and the lack of selective inhibitors. Current research suggests that GCNT3-targeted therapies, in combination with immunotherapy or chemotherapy, could improve treatment outcomes by modulating mucin production, tumor metabolism, and immune responses. This review critically explores GCNT3's diverse functions, its impact on cancer progression, and its potential as a therapeutic target, highlighting the need for cancer-specific approaches and future innovations in drug development to harness its clinical potential effectively.

Keywords:  Biomarker; Cancer; GCNT3; Metabolic reprogramming; O-linked glycosylation; Therapeutic resistance

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.144427
NPJ Precis Oncol. 2025 May 16. 9(1): 143

Hepatocellular carcinoma cells downregulate PGAM2 via SIRT2-mediated deacetylation modification to enhance aerobic glycolysis.

Zexuan Wang, Yaoyu Guo, Kefei Hu, Tingjiang He, Tong Qin, Ludan Zhang, Fang Xu, Yuanzhi Xu, Mingjiao Cheng, Jintao Zhang, Qianwei Zhao.

Phosphoglycerate mutase 2 (PGAM2) is a crucial glycolytic enzyme. Recently, we have found that both the protein and acetylation levels of PGAM2 are down-regulated in hepatocellular carcinoma (HCC) tissues. However, the functional significance of PGAM2 in HCC progression remains poorly characterized. In this study, we demonstrated that PGAM2 functioned as a tumor suppressor in HCC progression, and knockdown of PGAM2 promoted proliferation of HCC cells and tumor growth both in vitro and in vivo. Moreover, we identified lysine 100 (K100) in PGAM2 as the predominant deacetylation site of sirtuin-2 (SIRT2), and that deacetylation of K100 destabilized PGAM2 by promoting its ubiquitination and degradation. Importantly, we discovered that PGAM2 suppressed aerobic glycolysis through an enzymatic activity-independent mechanism in HCC cells. Mechanistic investigations revealed that PGAM2 knockdown upregulated lactate dehydrogenase A (LDHA) expression via activation of the signal transducer and activator of transcription 3 (STAT3). Furthermore, we found that knockdown of PGAM2 sensitized HCC cells to sorafenib treatment. In conclusion, these findings elucidate the tumor-suppressive role of PGAM2 in HCC progression and its post-translational regulation through SIRT2-mediated deacetylation, which provide novel biomarkers and therapeutic targets for HCC treatment.

DOI: https://doi.org/10.1038/s41698-025-00930-9
Anal Chem. 2025 May 21.

AIE-Active Probe for Unveiling the Role of Protein Sulfenylation In Vivo: Specific Imaging and Therapeutic Insights.

Xia Zhang, Jiaqi Yin, Guocheng Li, Wei Pan, Yanhua Li, Na Li, Bo Tang.

Protein sulfenylation (protein-SOH) is a central oxidation product of protein post-translational modification (PTM) that is crucial for signal transduction and cell behavior. However, the natural properties of protein-SOH, especially its low responsiveness and dynamic reversibility, pose a great challenge to the development of chemical probes to visualize protein-SOH in vivo. Here, we report an activated aggregation-induced emission (AIE) probe for specifically lighting-up protein-SOH in vivo. The AIE-active probe reacts with protein-SOH by nucleophilic substitution and exhibits intense fluorescence due to the restriction of intramolecular motion. The uniqueness of this probe ensures that fluorescence is only lighted up by protein-SOH, avoiding interference from small-molecule active substances and nonspecific adsorption of proteins. The significant increase of protein-SOH in atherosclerotic mice is detected by the AIE probe, and the level of protein-SOH positively correlates with atherosclerosis progression. Significantly, we find that specific binding of protein-SOH by this probe can inhibit plaque development, making it a promising therapeutic target. This study enables real-time imaging of protein oxidation modification in vivo, opening up a universal chemical tool for further elucidation of PTM and its role in signal transduction.

DOI: https://doi.org/10.1021/acs.analchem.5c00911
Free Radic Biol Med. 2025 May 21. pii: S0891-5849(25)00686-0. [Epub ahead of print]

Selenoprotein K-dependent MyD88 palmitoylation promotes hepatic metaflammation in high-fat diet fed mice.

Mengyue You, Yun Zhang, Meilin Gao, Wei Zhao, Li Wei, Xiong Z Ruan, Yaxi Chen.

  Metaflammation is characteristic of chronic metabolic inflammation, associated with increased risk of development of metabolic dysfunction-associated steatotic liver disease (MASLD). Palmitoylation of Myeloid differentiation factor 88 (MyD88) adaptor protein mediates biologically important signal transduction pathways in inflammatory responses. However, the molecular mechanisms underlying MyD88 palmitoylation contributes to lipid-induced metaflammation in the progression of MASLD is not completely understood. In this study, an increment of MyD88 palmitoylation was observed in the livers of high-fat diet fed mice, accompanied by increased lipid accumulation and an inflammatory response. Inhibition of MyD88 palmitoylation attenuated the inflammation and hepatic steatosis in HFD-induced mice. Mechanistically, palmitoylation of MyD88 activated NF-κB-p65 and p38 MAPK signals in a selenoprotein K (SelK)-DHHC6 palmitoyltransferase complex dependent pathway. Intervention of SelK SH3 binding domain reduced the palmitoylation level of MyD88 by inhibiting the interaction between SelK and DHHC6. Our findings suggest that MyD88 palmitoylation regulates the metabolic disorder and metaflammation through SelK/DHHC6-dependent pathway, cooperatively. Inhibition of MyD88 palmitoylation and SelK SH3 binding domain may represent a new therapeutic strategy for treatment of MASLD progression.

Keywords:  MASLD; Metaflammation; MyD88; Palmitoylation; Selenoprotein K

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.403
Autophagy. 2025 May 20.

S-palmitoylation coordinates the trafficking of ATG9A to mediate autophagy initiation.

Fan Xia, Weining Li, Wenru Wang, Jiru Liu, Xiaolin Li, Jing Cai, Hao Shan, Zhe Cai, Jun Cui.

  Macroautophagy (hereafter autophagy), a major intracellular catabolic process, is evolutionarily conserved from yeasts to mammals, and is associated with a broad range of human diseases. Autophagy is morphologically characterized by the formation of double-membrane autophagosomes. ATG9A, a multi-spanning transmembrane protein and lipid scramblase, is a core component of the autophagy machinery that complements membrane sources and equilibrates lipids across membrane bilayers. Here, we report that palmitoyltransferase ZDHHC5 is indispensable for autophagosome nucleation and subsequent autophagosome formation. Upon autophagy induction, ZDHHC5 is internalized from the plasma membrane into intracellular compartments via clathrin-mediated endocytosis. This enzyme activates ATG9A S-palmitoylation at cysteine 155/156, which orchestrates the interaction of ATG9A with the heterotetrameric adaptor protein complex family member AP4E1/AP-4ε and subsequent trafficking from the trans-Golgi network to endosomal compartments. Functionally, impairment of ATG9A S-palmitoylation results in defects in autophagy initiation and autophagosome formation. These findings identify a regulatory mechanism that coordinates ATG9A-binding with AP4E1 and vesicular trafficking events through ATG9A S-palmitoylation by ZDHHC5, thereby ensuring the spatiotemporal fidelity of membrane trafficking and maintenance of autophagic homeostasis.

Keywords:  AP4E1; Trans-golgi network; ZDHHC5; autophagosome formation; clathrin-mediated endocytosis; membrane trafficking

DOI:  https://doi.org/10.1080/15548627.2025.2509376
Am J Hypertens. 2025 May 17. pii: hpaf084. [Epub ahead of print]

OGT-mediated O-GlcNAc of PINK1 promotes the progression of obesity-related hypertension via regulating mitophagy.

Xiaoling Zeng, Shengjiao Liang.

   BACKGROUND: Obesity causes a variety of metabolic diseases, including hypertension. O-linked beta-N-acetylglucosamine (O-GlcNAc), a dynamic post-translational modification, is rapidly cycled on and off proteins by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Our study hypothesized that O-GlcNAc contributes to the progression of obesity-related hypertension (OH). Using in vivo and in vitro approaches, we systematically investigated the role of O-GlcNAc in OH pathogenesis and elucidated its molecular mechanisms.
METHODS: An in vivo OH rat model was established through feeding with a high-fat diet. Besides, A7r5 cells were treated with oxidized low-density lipoprotein (ox-LDL) to simulate OH in vitro. Western blot was used to detect the protein levels of O-GlcNAc, OGT, OGA, and autophagy-related indicators. CCK-8 was performed to analyze the cell viability. The apoptosis rate was assessed by flow cytometry. Co-immunoprecipitation was performed to verify the endogenous interaction between OGT and PTEN-induced putative kinase (PINK)1.
RESULTS: OGT-mediated O-GlcNAc was elevated in both in vivo and in vitro OH models. Besides, OGT deficiency inhibited hypertension and inflammation, and increased autophagy in high-fat diet-induced OH rats. Additionally, OGT inhibition increased cell viability and autophagy and inhibited apoptosis in ox-LDL-treated A7r5 cells. Mechanically, OGT-mediated O-GlcNAc of PINK1 at S335 site regulated the phosphorylation of PINK1. Finally, PINK1 inhibition decreased cell viability and autophagy and promoted apoptosis in ox-LDL-treated A7r5 cells.
CONCLUSION: OGT-mediated O-GlcNAc of PINK1 promoted the progression of OH via regulating mitophagy, which might provide a new insight for OH treatment.

Keywords:  O-GlcNAc; OGT; PINK1; mitophagy; obesity-related hypertension

DOI:  https://doi.org/10.1093/ajh/hpaf084