查找使用阿拉丁产品的科研文献

YTHDF1-mediated m6A modification promotes cisplatin resistance in ovarian cancer via the FZD7/Wnt/β-catenin pathway

Miao Jintian,Jiang Xinyan,Wang Siyun

Cisplatin resistance significantly hinders the efficacy of ovarian cancer treatment, presenting a major challenge in improving patient outcomes. This study identifies the m6A reader protein YTHDF1 as a key regulator of cisplatin resistance in ovarian cancer through its modulation of the FZD7/Wnt/β-catenin signaling pathway. Using cisplatin-resistant ovarian cancer cell lines (A2780/DDP and SKOV3/DDP), we observed elevated YTHDF1 expression, which positively correlated with tumor cell proliferation and migration. Silencing YTHDF1 reduced FZD7 expression, inhibited Wnt/β-catenin signaling, and restored cisplatin sensitivity both in vitro and in vivo. Mechanistic investigations revealed that YTHDF1 binds to m6A-modified FZD7 mRNA, enhancing its stability and translation. Functional studies in xenograft mouse models demonstrated that targeting YTHDF1 suppressed tumor growth and enhanced apoptosis in cisplatin-resistant ovarian cancer cells. These findings highlight the YTHDF1-FZD7 axis as a novel therapeutic target for overcoming cisplatin resistance, paving the way for improved treatment strategies in ovarian cancer.

YTHDF1-targeting nanoassembly reverses tumoral immune evasion through epigenetics and cell cycle modulation

Hongting Liu,Xichu Zhang,Fangchun Ding,Jingfang Pan,Hanxiang Zhu,Zhanwei Zhou,Minjie Sun

YTHDF1, as a key m 6 A reader protein, is believed to be one of the key mechanisms leading to tumor cell immune evasion and resistance via promoting MHC-I degradation. We explore therapeutic strategies that combine iron metabolism regulation with epigenetic regulation. Here, a nanoassembly that integrates Deferasirox (DFX, an FDA-approved iron chelator) and YTHDF1 siRNA (known as PPD/siYTHDF1) has been developed, which jointly promotes cell cycle arrest in tumor cells by interfering with iron metabolism and knocking down YTHDF1 protein. At the same time, YTHDF1 deficiency inhibits the mRNA translation of lysosome-related proteins, upregulates MHC-I molecule expression (2.5-fold), reduces the degradation of internalized antigens, enhances T cell-mediated immune response, and ultimately restores tumor immune surveillance and triggers powerful anti-tumor immune efficacy. After treatment, CD8 + T cells in the tumor site increased by 2.2-fold, and effector memory T cells in the spleen increased by 2.1-fold. It demonstrates a highly effective anti-tumor effect in breast cancer treatment, as well as in postoperative anti-recurrence and anti-metastasis models.

Photosensitive and dual-targeted chromium nanoparticle delivering small interfering RNA YTHDF1 for molecular-targeted immunotherapy in liver cancer

Chen Shang,He Yan,Huang Xin,Shen Yao,Zou Qingshuang,Yang Gun,Fu Li,Liu Quan,Luo Dixian

Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application. Graphical Abstract

Curcumin prevents obesity by targeting TRAF4-induced ubiquitylation in m6A-dependent manner

Yushi Chen,Ruifan Wu,Wei Chen,Youhua Liu,Xing Liao,Botao Zeng,Guanqun Guo,Fangfang Lou,Yun Xiang,Yizhen Wang,Xinxia Wang

Obesity has become a major health problem that has rapidly prevailed over the past several decades worldwide. Curcumin, a natural polyphenolic compound present in turmeric, has been shown to have a protective effect on against obesity and metabolic diseases. However, its underlying mechanism remains largely unknown. Here, we show that the administration of curcumin significantly prevents HFD-induced obesity and decreases the fat mass of the subcutaneous inguinal WAT (iWAT) and visceral epididymal WAT (eWAT) in mice. Mechanistically, curcumin inhibits adipogenesis by reducing the expression of AlkB homolog 5 (ALKHB5), an m6A demethylase, which leads to higher m6A-modified TNF receptor-associated factor 4 (TRAF4) mRNA. TRAF4 mRNA with higher m6A level is recognized and bound by YTHDF1, leading to enhanced translation of TRAF4. TRAF4, acting as an E3 RING ubiquitin ligase, promotes degradation of adipocyte differentiation regulator PPARγ by a ubiquitin–proteasome pathway thereby inhibiting adipogenesis. Thus, m6A-dependent TRAF4 expression upregulation by ALKBH5 and YTHDF1 contributes to curcumin-induced obesity prevention. Our findings provide mechanistic insights into how m6A is involved in the anti-obesity effect of curcumin.

YTHDF1 modulates CAP1-mediated actin turnover to regulate synaptic function and anxiodepressive-like behaviors

Zhou Xidan,Li Si,Guo Chen,Wu Songfen,Wu Xiaoli,Wu Min,Wu Cuiting,Li Kuan,Cui Yihui,Zhou Tao

Neuroplasticity and synaptic dysfunction are central to the pathophysiology of depression, yet their underlying mechanisms remain not fully understood. Here, we identify the m 6 A reader protein YTHDF1 as a key regulator of depression pathogenesis. Mice with genetic deletion of Ythdf1 exhibited anterior cingulate cortex (ACC) hyperactivity, hyperalgesia, heightened social stress sensitivity, and anxiodepressive-like behaviors following acute social stress. Using multi-omics approaches, we linked these effects to dysregulated actin cytoskeleton dynamics and identified cyclase-associated protein 1 (CAP1) as a downstream effector of YTHDF1. YTHDF1 deficiency reduced CAP1 expression from early postnatal stages, leading to F-actin accumulation, impaired synaptic function, and behavioral deficits. Strikingly, early postnatal re-expression of YTHDF1 in the ACC normalized CAP1 levels, restored synaptic integrity, and reversed depressive-like phenotypes. Similarly, CAP1 re-expression was sufficient to alleviate stress-induced psychomotor retardation and anxiety. Our findings establish the YTHDF1-CAP1 axis as a critical pathway governing synaptic function and depressive behaviors.

Manganese-based microcrystals equipped with Ythdf1-targeted biomimetic nanovaccines for reinforced dendritic cell spatiotemporal orchestration

Feng Liu,Lulu Tan,Zheng Dai,Yang Wang,Lei Huang,Yang Zhang,Qian Cheng,Xin Li,Miao-Deng Liu,Lin Wang,Zheng Wang

Undesired dendritic cell (DC) spatiotemporal orchestration and innate immune stimulation severely dampens anti-tumor efficacy of cancer vaccines. Here, we develop a manganese-based (Mn 2+ ) metal-organic framework (MOF) microcrystal equipped with Ythdf1-targeted biomimetic nanovaccines to create an in situ proinflammatory immune niche for augmented DC spatiotemporal orchestration. The bimetallic MOF microcrystal serves as a self-adjuvanting delivery platform that cannot only gradually release tumor-associated antigens and Mn 2+ , but also create an in situ immune niche for DC spatiotemporal orchestration including recruitment (particularly for DC1s, cross-presenting antigens to CD8 + T cells), activation, and lymph node migration. Benefitting from the Mn 2+ -mediated cGAS-STING activation together with Ythdf1 downregulation-induced antigen cross-presentation reinforcement, the vaccines elicit robust prophylactic efficacy for delaying B16-OVA and MC38 tumor occurrence, and show potent therapeutic efficacy for suppressing postoperative MC38 tumor recurrence and metachronous liver metastasis. Our study provides a versatile and powerful approach for fabricating personalized scaffold cancer vaccines.

WTAP Histone Lactylation Drives the YTHDF1/ALOX15 Axis to Regulate Ferroptosis in Myocardial Ischemia–Reperfusion Injury

Wei Liu,Yuqin Wang,Jiayuan Wu,Caihong He,Zhengwei Zhou

Lactate, a metabolic byproduct of glycolysis, accumulates during myocardial infarction and ischemia/reperfusion (I/R) injury, acting as both a metabolic stress marker and a signaling molecule that influences inflammation and cell fate. Lactate can induce histone lysine lactylation (Kla), a novel post‐translational modification that regulates gene transcription and immune responses. Despite this discovery, its role in I/R injury remains unclear. To investigate the effects of lactate and histone lactylation, both in vivo myocardial I/R injury and in vitro hypoxia/reoxygenation (H/R) injury models using cardiomyocytes were established. Lipid peroxidation, LDH, MDA, SOD, and iron levels were quantified using specialized fluorescent probes and commercial kits. MeRIP and RIP assays were performed to investigate WTAP, YTHDF1, and ALOX15 interactions. TEM was utilized to examine mitochondrial ultrastructure and morphology. Lactate levels were elevated in I/R rats, and reducing lactate levels effectively mitigated ferroptosis and myocardial injury. Furthermore, lactate promoted Kla of WTAP, resulting in upregulation of WTAP protein expression compared to the I/R group. Global m 6 A RNA methylation levels increased by lactate treatment. Elevated WTAP levels, or overexpression of YTHDF1, facilitated m6A modification of ALOX15 mRNA, leading to upregulation of ALOX15 expression and enhanced ferroptosis during I/R injury. Notably, overexpression of ALOX15 reversed the protective effects of WTAP knockdown. Finally, we validated the involvement of the WTAP‐YTHDF1‐ALOX15 regulatory axis in vivo. Lactate‐induced Kla of WTAP led to its upregulation, which, together with YTHDF1, facilitated the m6A modification of ALOX15 mRNA. This modification increased ALOX15 expression, triggering cardiomyocyte ferroptosis and worsening myocardial I/R injury. These findings highlight the potential of targeting lactate‐induced Kla and its downstream effectors, including WTAP, YTHDF1, and ALOX15, as therapeutic strategies. Lactate accumulation during myocardial ischemia–reperfusion injury enhances histone lactylation and WTAP expression, promoting m 6 A modification of ALOX15 mRNA through YTHDF1. This regulatory axis increases ALOX15 expression, lipid peroxidation, and ferroptosis, thereby aggravating myocardial injury. Targeting WTAP lactylation or the WTAP/YTHDF1/ALOX15 pathway may provide a potential therapeutic strategy for myocardial ischemia–reperfusion injury.

YTHDF1 regulates the proliferation and differentiation of keratinocytes via the PI3K/AKT signaling pathway in atopic dermatitis

Maoxin Huang,Liping Dong,Yue He,Xinying Cai,Yun Lu,Jinlei Xu,Fengli Xiao

Background YTHDF1, a critical regulator of cellular processes, has attracted attention for its involvement in some inflammatory diseases. However, its specific association with atopic dermatitis (AD) remains unclear. The objective is to investigate the functional roles and underlying mechanisms of YTHDF1 in AD. Methods The expression of YTHDF1 was investigated by bioinformatics analysis and skin lesions of AD patients. The functional role and upstream and downstream regulatory mechanisms of YTHDF1 were examined through a series of in vitro and in vivo experiments. Adeno-associated virus (AAV)-mediated delivery of YTHDF1 in the AD mouse model was evaluated for its therapeutic potential. Results Bioinformatics analysis revealed that the YTHDF1 mRNA level in the skin lesions of AD was significantly higher than that in healthy people. YTHDF1 expression was significantly elevated in AD skin lesions, the DNCB-induced AD mouse model, and primary human keratinocytes and HaCaT cells stimulated with interleukin (IL)-4/IL-13, compared to controls. Both in vitro and in vivo experiments revealed that upregulation of YTHDF1 in AD exacerbated cell proliferation and inhibited keratinization by activating the PI3K/AKT pathway, which was modulated via the IL-4/IL-13/STAT3 axis. Moreover, topical application of AAV-YTHDF1 significantly improved AD-like lesions in the mouse model. Conclusions This study identifies YTHDF1 as a contributor to AD pathogenesis by influencing keratinocyte proliferation and differentiation. It also suggests that YTHDF1 could be a potential therapeutic target for AD treatment.

NBR1-mediated autophagic degradation of YTHDF1 curtails FDX1 translation to drive concurrent multikinase inhibitor resistance and cuproptosis tolerance

Weikai Wang,Xin Jiang,Xiaona Chen,Kaiyu Liang,Miaoqin Chen,Kaizhong Lu,Qi Wei,Yuchen Wu,Liyuan Zhu,Yuan Chen,Tianlun Hou,Jingfeng Luo,Chentao Li,Xian Wang,Hongchuan Jin,Lifeng Feng

MCM10, regulated by METTL3/ YTHDF1-mediated m6A modification, contributes to colorectal cancer progression through induction of M2 macrophage polarization

Qu Qiao,Li Zhilong,Wang Dalu,Wu Di,Yin Hongzhuan

Colorectal cancer (CRC) remains a major contributor to cancer-related mortality worldwide. Although minichromosome maintenance protein 10 (MCM10) is known for its role in DNA replication, its involvement in CRC progression has not been fully elucidated. To identify key oncogenic drivers, RNA sequencing was performed on seven paired CRC and adjacent normal tissues, revealing significant upregulation of MCM10 (Log2FC = 2.359, P  = 0.003). Public GEO datasets (GSE240623, GSE200427) further confirmed MCM10 overexpression in CRC tissues. This finding was validated in 40 paired clinical samples using qPCR and Western blotting. Prognostic relevance was assessed using hazard ratio (HR). Functional assays in vitro and in vivo were conducted to assess the effects of MCM10 on proliferation, migration, invasion, and M2 macrophage polarization. The m6A modification of MCM10 mRNA was evaluated through METTL3 and YTHDF1 interaction analysis in HCT116 cells. MCM10 was significantly upregulated in CRC tissues and associated with poor prognosis (HR = 1.54, P  = 0.00077). MCM10 overexpression promoted CRC cell proliferation and invasion and was correlated with elevated M2 macrophage infiltration in tumor xenografts (6.16 ± 0.85% vs. 11.7 ± 1.13%, P  < 0.05). Conditioned media from MCM10-overexpressing cells enhanced THP-1 macrophage polarization by increasing secretion of CCL2, CCL5, and IL10. Mechanistically, METTL3-mediated m6A modification stabilized MCM10 mRNA in a YTHDF1-dependent manner. MCM10 is aberrantly overexpressed in CRC and linked to worse clinical outcomes. Its oncogenic effects involve METTL3/YTHDF1-mediated mRNA stabilization and enhanced M2 macrophage polarization, suggesting a potential role in immune microenvironment modulation.

m6A-modified EHD1 controls PD-L1 endosomal trafficking to modulate immune evasion and immunotherapy responses in lung adenocarcinoma

Fanglin Tian,Jian Huang,Weina Fan,Xin Li,Yuning Zhan,Kexin Zhu,Xiangyu Wang,Xin Hong,Xin Wang,Jin Ren,Ying Xing,Li Cai

Background Eps15 homology domain (EHD) proteins, including EHD1 to EHD4, play vital roles in tumor progression. In this study, we aimed to investigate which specific EHD proteins, if any, are implicated in tumor immune evasion and immunotherapy response. Methods The immunotherapy responses of lung adenocarcinoma (LUAD) patients were predicted using tumor immune dysfunction and exclusion (TIDE) analysis. The T cell killing assay was performed by co-culturing activated T cells with LUAD cells. The function of EHD1 as a regulator of programmed death-ligand 1 (PD-L1) endocytic recycling was determined by receptor internalization assays. Methylated RNA immunoprecipitation (MeRIP) was performed to investigate N6-methyladenosine (m 6 A) modification of EHD1 mRNA. The protein-protein interaction was revealed by the molecular docking analysis and validated by immunofluorescence (IF) and immunoprecipitation (IP) assays. RNA immunoprecipitation (RIP) was used to examine the interaction between YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) and EHD1 mRNA. The regulatory mechanism of YTHDF1 on EHD1 was investigated through the application of m 6 A-binding site mutation analysis. The murine LUAD cells were employed to establish subcutaneous xenograft models within immunocompetent C57BL/6 mice to assess the immunomodulatory impact of EHD1 in vivo. Results TIDE algorithms and survival analysis identified that EHD1 promoted LUAD immune escape. EHD1 knockdown enhanced T cell cytotoxicity in killing LUAD cells across all effector-to-target (E/T) ratios. EHD1 overexpression exerted the opposite effect. The molecular docking analysis revealed an interaction between EHD1 and the PD-L1 protein, verified by IF and IP. Furthermore, EHD1 knockdown inhibited PD-L1 recycling, thereby promoting its lysosomal degradation. Disruption of the EHD1/PD-L1 interaction impaired the regulatory function of EHD1 in tumor immune evasion. In an immune-competent mouse model, we found that EHD1 silencing impeded tumor immune evasion and enhanced the efficacy of anti‑PD‑1 therapy. MeRIP-qPCR confirmed obvious m 6 A modification of EHD1 . Further, the EHD1 mRNA was found to bind to the YTHDF1 protein, an m 6 A reader. YTHDF1 overexpression up-regulated EHD1 expression by enhancing its mRNA stability in an m 6 A-dependent manner. Conclusion Our study illuminates the role of m 6 A-modified EHD1 in tumor immune evasion and immunotherapy responses, thereby offering a novel avenue to potentially enhance immunotherapeutic sensitivity and improve the prognosis for patients with LUAD.

Diosmetin-7-O-β-D-glucopyranoside from Pogostemonis Herba alleviated SARS-CoV-2-induced pneumonia by reshaping macrophage polarization and limiting viral replication

Yun-Lu Xu,Xue-Jian Li,Wei Cai,Wen-Ying Yu,Jing Chen,Qin Lee,Yong-Jun Choi,Fang Wu,Ying-Jun Lou,Hua-Zhong Ying,Chen-Huan Yu,Qiao-Feng Wu

Ethnopharmacological relevance Viral pneumonia is the leading cause of death after SARS-CoV-2 infection. Despite effective at early stage, long-term treatment with glucocorticoids can lead to a variety of adverse effects and limited benefits. The Chinese traditional herb Pogostemonis Herba is the aerial part of Pogostemon Cablin (Blanco) Benth., which has potent antiviral, antibacterial, anti-inflammatory, and anticancer effects. It was used widely for treating various throat and respiratory diseases, including COVID-19, viral infection, cough, allergic asthma, acute lung injury and lung cancer. Aim of the study To investigate the antiviral and anti-inflammatory effects of chemical compounds from Pogostemonis Herba in SARS-CoV-2-infected hACE2-overexpressing mouse macrophage RAW264.7 cells and hACE2 transgenic mice. Materials and methods The hACE2-overexpressing RAW264.7 cells were exposed with SARS-CoV-2. The cell viability was detected by CCK8 assay and cell apoptotic rate was by flow cytometric assay. The expressions of macrophage M1 phenotype markers (TNF-α and IL-6) and M2 markers (IL-10 and Arg-1) as well as the viral loads were detected by qPCR. The mice were inoculated intranasally with SARS-CoV-2 omicron variant to induce viral pneumonia. The levels of macrophages, neutrophils, and T cells in the lung tissues of infected mice were analyzed by full spectrum flow cytometry. The expressions of key proteins were detected by western blot assay. Results Diosmetin-7-O-β-D-glucopyranoside (DG) presented the strongest anti-SARS-CoV-2 activity. Intervention with DG at the concentrations of 1.25-50 μM not only reduced the viral replication, cell apoptosis, and the productions of inflammatory cytokines (IL-6 and TNF-α) in SARS-CoV-2-infected RAW264.7 cells, but also reversed macrophage polarity from M1 to M2 phenotype. Furthermore, treatment with DG (25-100 mg/kg) alleviated acute lung injury, and reduced macrophage infiltration in SARS-COV-2-infected mice. Mechanistically, DG inhibited SARS-COV-2 gene expression and HK3 translation via targeting YTHDF1, resulting in the inactivation of glycolysis-mediated NF-κB pathway. Conclusions DG exerted the potent antiviral and anti-inflammatory activities. It reduced pneumonia in SARS-COV-2-infected mice via inhibiting the viral replication and accelerating M2 macrophage polarization via targeting YTHDF1, indicating its potential for COVID-19 treatment.