PHYTOMEDICINE
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2025
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IF 8.3
Xue-Ting Xu,Jun-Kai Fan,Xi Chen,Si-Yi Que,Run-Xin Zhang,Yu-Yan Xie,Tian-Ci Zhou,Kunmei Ji,Zhen-Fu Zhao,Jia-Jie Chen
Background Mast cells (MCs) mediate high-affinity IgE Fc receptor (FcεRI)-mediated allergic reactions. Royal jelly acid (RJA), the major lipid constituent of royal jelly, has anti-inflammatory, anti-tumor, antibacterial, and immunomodulatory properties. Purpose This study aimed to investigate how RJA affects IgE-mediated MC activation and to elucidate mechanisms underlying anti-allergic effects. Methods Mouse bone marrow-derived mast cells (BMMCs) and rat basophilic leukemia cells-2H3 (RBLs) were stimulated with IgE-antigen (Ag). β-hexosaminidase (β-hex) and histamine (HA) release, inflammatory cytokines expression, and cellular morphology changes were examined in stimulated cells. Transcriptome changes associated with RJA-treated activated-MCs were analyzed. Network pharmacology, gene expression, and western blot analyses were employed to explore the relationship between H3 lactylation and anti-allergic effects of RJA on MC. In vivo studies were conducted in IgE-mediated passive cutaneous anaphylaxis (PCA), ovalbumin (OVA)-induced active systemic anaphylaxis (ASA), and HA-induced passive systemic anaphylaxis (PSA) mouse models. Results RJA inhibited IgE-dependent MC activation as evidenced by reduced β-hex and HA release. RJA inhibited MAPK and NF-κB signaling, down-regulated RELA and NFκB1 transcripts, and decreased NF-κB reporter activity. RJA inhibited cellular H3 lactylation and H3K9 lactylation (H3K9la), leading to reduced histone lactyllysine enrichment in RELA or NFκB1 promoter loci. RJA alleviated allergic symptoms in PCA and ASA mice by intraperitoneal injection or oral administration, but did not affect HA-induced hypothermia. Conclusion RJA inhibits IgE-dependent MC activation by reducing cellular H3K9la and suppressing NF-κB signaling via reduced histone lactyllysine enrichment in RELA or NFκB1 promoter sites. RJA may support MC inhibition in the prevention and treatment of allergic diseases.
研究领域:
免疫学
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过敏与免疫疾病
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分子生物学
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表观遗传学
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药理学
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转化医学
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DOI
PubMed
高影响因子
Biology Direct
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2025
·Vol. 20
·期 1
·1-15
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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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DOI
PubMed
高影响因子
Advanced Science
·
2025
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IF 14.1
Runyu Dong,Yao Fei,Yiren He,Peng Gao,Bo Zhang,Menglin Zhu,Zhixiong Wang,Longfei Wu,Shuai Wu,Xiaoming Wang,Juan Cai,Zhiqiang Chen,Xueliang Zuo
Drug resistance remains a major hurdle for the therapeutic efficacy of lenvatinib in hepatocellular carcinoma (HCC). However, the underlying mechanisms remain largely undetermined. Unbiased proteomic screening is performed to identify the potential regulators of lenvatinib resistance in HCC. Patient-derived organoids, patient-derived xenograft mouse models, and DEN/CCl 4 induced HCC models are constructed to evaluate the effects of HECTD2 both in vitro and in vivo. HECTD2 is found to be highly expressed in lenvatinib-resistant HCC cell lines, patient tissues, and patient-derived organoids and xenografts. In vitro and in vivo experiments demonstrated that overexpression of HECTD2 limits the response of HCC to lenvatinib treatment. Mechanistically, HECTD2 functions as an E3 ubiquitin ligase of KEAP1, which contributes to the degradation of KEAP1 protein. Subsequently, the KEAP1/NRF2 signaling pathway initiates the antioxidative response of HCC cells. Lactylation of histone 3 on lysine residue 18 facilitates the transcription of HECTD2. Notably, a PLGA-PEG nanoparticle-based drug delivery system is synthesized, effectively targeting HECTD2 in vivo. The NPs achieved tumor-targeting, controlled-release, and biocompatibility, making them a promising therapeutic strategy for mitigating lenvatinib resistance. This study identifies HECTD2 as a nanotherapeutic target for overcoming lenvatinib resistance, providing a theoretical basis and translational application for HCC treatment.
研究领域:
肿瘤学
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分子生物学
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药物研发
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纳米医学
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DOI
PubMed
高影响因子
Antioxidants
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2024
·Vol. 13
·期 2
·176
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IF 6
Ren Zhou,Rui-Chen Ding,Qian Yu,Cheng-Zeng Qiu,Hao-Yi Zhang,Zong-Jun Yin,Da-Long Ren
Beyond its well-established role in diabetes management, metformin has gained attention as a promising therapeutic for inflammation-related diseases, largely due to its antioxidant capabilities. However, the mechanistic underpinnings of this effect remain elusive. Using in vivo zebrafish models of inflammation, we explored the impact of metformin on neutrophil recruitment and the underlying mechanisms involved. Our data indicate that metformin reduces histone (H3K18) lactylation, leading to the decreased production of reactive oxygen species (ROS) and a muted neutrophil response to both caudal fin injury and otic vesicle inflammation. To investigate the precise mechanisms through which metformin modulates neutrophil migration via ROS and H3K18 lactylation, we meticulously established the correlation between metformin-induced suppression of H3K18 lactylation and ROS levels. Through supplementary experiments involving the restoration of lactate and ROS, our findings demonstrated that elevated levels of both lactate and ROS significantly promoted the inflammatory response in zebrafish. Collectively, our study illuminates previously unexplored avenues of metformin’s antioxidant and anti-inflammatory actions through the downregulation of H3K18 lactylation and ROS production, highlighting the crucial role of epigenetic regulation in inflammation and pointing to metformin’s potential in treating inflammation-associated conditions.Keywords:ROS;metformin;neutrophil recruitment;H3K18 lactylation;zebrafish
研究领域:
药理学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
STAR Protocols
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2025
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IF 1.3
Yu Ran,Qiqing Yang,Lianqi Zhou,Heyu Li,Bing Yang,Long Zhang
Summary L-lactate has been recognized as an essential molecule for signaling and metabolic balance. Lactylation, a post-translational modification (PTM) derived from L-lactate, is commonly observed on various proteins and plays essential roles in cellular processes. Here, we present a protocol to globally profile the lactylation proteome and perform label-free quantification. We provide steps for cell preparation, protein extraction, digestion, peptide desalting, and lactylpeptide enrichment. Additionally, we outline the parameters for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. For complete details on the use and execution of this protocol, please refer to Li et al. 1
研究领域:
生物化学
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蛋白质组学
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分子生物学
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PubMed
高影响因子
Nature Communications
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2025
·Vol. 16
·期 1
·1-19
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IF 15.7
Shen Xuecheng,Qiao Wenxuan,Yan Wei,Xie Hao,Zhang Chenyang,Sun Yang,Luo Qiong,Xu Qiang
IL-17 signaling contributes to the pathogenesis of psoriasis; however, IL-17 involvement in keratinocyte hyperactivation of epidermis remains unclear. Here, we describe an IL-17A-induced, skin-specific, positive feedback loop, which operates independently of canonical chemokine production, thus untangling skin inflammation and epithelial hyperproliferation in psoriasis. We show that IL-17A-induced, keratinocyte-specific KLK8 interacts with IL-17R to promote histone H4 lysine lactylation (H4K12la) catalyzed by the acetyltransferase HAT1. H4K12la further promotes IL-17A-mediated keratinocyte proliferation and the expression of KLK8 and IL-17R, creating a feedback loop that drives psoriasis progression. Importantly, excessive lactate in the microenvironment exacerbates H4K12la and psoriasis severity, thereby impairing the efficacy of anti-IL-17A antibody. Silencing KLK8, HAT1, or inhibiting lactate accumulation attenuates psoriasis in mice. Moreover, combining lactylation inhibition with anti-IL-17A therapy exhibits synergistic effects against antibody-resistant psoriasis. Thus, our findings unveil a lactylation-driven, keratinocyte-specific IL-17A signaling and offer a promising approach for psoriasis treatment, particularly in patients with comorbid metabolic syndrome.
研究领域:
皮肤生物学
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表观遗传学
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免疫学
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分子生物学
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炎症性疾病
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转化医学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Yuangui Tang,Chenyun Dai,Huihui Yang,Xian Yang,Ziyu Chen,Jinxiu Dou,Liuxu Zhang,Tao Bai,Junfang Zheng
Non-histone proteins localized in membrane, cytosol and nucleus are lactylated to promote tumor progression. However, whether mitochondrial proteins undergo lactylation and contribute to tumor progression remains unexplored. Here, we identified multiple lactylated mitochondrial proteins in human renal cell carcinoma (RCC) cells using lactylome profiling. Among these, malate dehydrogenase 2 (MDH2)–the only lactylated protein in the tricarboxylic acid (TCA) cycle–emerged as a key target, with K239 as its lactylation site. MDH2 K239la levels are regulated by KAT8 and SIRT3. Under low-glucose, high-lactate conditions mimicking the tumor microenvironment, MDH2 K239la elevated the NADH/NAD + ratio to drive ATP production and boosted NADPH generation to reduce ROS. This enables cells to alleviate oxidative stress, sustain mitochondrial function, and promote RCC malignancy in vitro and in vivo . Mechanistically, MDH2 K239la enhances MDH2 enzymatic activity and strengthens its interaction with the citrate transporter SLC25A1. This facilitates citrate efflux, fueling IDH1-dependent NADPH production when lactate serves as an energy source. Collectively, we unveil a lactylation-dependent mechanism that reprograms mitochondrial metabolism to confer oxidative stress resistance and drive RCC progression. Targeting mitochondrial proteins lactylation, exemplified by MDH2 K239la , represents a promising therapeutic strategy for RCC.
研究领域:
癌症生物学
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生物化学
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细胞生物学
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分子生物学
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代谢工程
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肿瘤学
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DOI
PubMed
高影响因子
Advanced Science
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2025
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IF 14.1
Zengyu Zhang,Shanshan Huang,Yong Wang,Zhiwen Jiang,Zhuohang Liu,Chenran Wang,Rong Ji,Yiwen Yuan,Xueyu Mao,Kaicheng Yang,Huicong Niu,Yanqin Gao,Jing Zhao
Microglial metabolic/inflammatory reprogramming critically influences stroke outcomes, yet its mechanisms remain poorly understood. Lysine lactylation, an epigenetic modification in which lactate-derived lactyl groups modify lysine residues, regulates immune and neurological processes. Here, lysine lactylation is identified as a key link between ischemic metabolic stress and microglial dysfunction. Stroke-induced lactate accumulation drives microglial protein lactylation, which correlates with poor neurological outcomes. Proteomics identified that methyl-CpG binding protein 2 (MeCP2) is lactylated at lysine 210 (K210), enhancing its transcriptional activation of glycolytic/inflammatory genes, especially hexokinase 2 (HK2). HK2 overexpression mimics lactylation-induced pathology (mitochondrial dysfunction, glycolytic shift, inflammation), while knockdown reverses these effects. Lactylated MeCP2 impairs mitochondrial respiration, disrupts metabolic signaling (leading to dysregulated activation of the mammalian target of rapamycin (mTOR)/AMPK pathway), and sustains neuroinflammation. Genetic ablation of MeCP2-K210 lactylation (via K210R mutation), pharmacological inhibition of lactyltransferase p300, or HK2 inhibition with lonidamine restores mitochondrial function, attenuates neuroinflammation, and improves neurofunctional recovery. The findings establish MeCP2-K210 lactylation as a critical metabolic-epigenetic switch driving microglial activation via the HK2/mTOR axis, identifying a therapeutic target for postischemic neuroinflammation.
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高影响因子
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