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Background Ocular neovascularization is a leading cause of blindness. Retinal microglia have been implicated in hypoxia-induced angiogenesis and vasculopathy, but the underlying mechanisms are not entirely clear. Lactylation is a novel lactate-derived posttranslational modification that plays key roles in multiple cellular processes. Since hypoxia in ischemic retinopathy is a precipitating factor for retinal neovascularization, lactylation is very likely to be involved in this process. The present study aimed to explore the role of lactylation in retinal neovascularization and identify new therapeutic targets for retinal neovascular diseases. Results Microglial depletion by the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX3397 suppresses retinal neovascularization in oxygen-induced retinopathy. Hypoxia increased lactylation in microglia and accelerates FGF2 expression, promoting retinal neovascularization. We identify 77 sites of 67 proteins with increased lactylation in the context of increased lactate under hypoxia. Our results show that the nonhistone protein Yin Yang-1 (YY1), a transcription factor, is lactylated at lysine 183 (K183), which is regulated by p300. Hyperlactylated YY1 directly enhances FGF2 transcription and promotes angiogenesis. YY1 mutation at K183 eliminates these effects. Overexpression of p300 increases YY1 lactylation and enhances angiogenesis in vitro and administration of the p300 inhibitor A485 greatly suppresses vascularization in vivo and in vitro. Conclusions Our results suggest that YY1 lactylation in microglia plays an important role in retinal neovascularization by upregulating FGF2 expression. Targeting the lactate/p300/YY1 lactylation/FGF2 axis may provide new therapeutic targets for proliferative retinopathies.

Direct neuronal reprogramming is a promising approach to regenerate neurons from local glial cells. However, mechanisms of epigenome remodeling and co-factors facilitating this process are unclear. In this study, we combined single-cell multiomics with genome-wide profiling of three-dimensional nuclear architecture and DNA methylation in mouse astrocyte-to-neuron reprogramming mediated by Neurogenin2 (Ngn2) and its phosphorylation-resistant form (PmutNgn2), respectively. We show that Ngn2 drives multilayered chromatin remodeling at dynamic enhancer–gene interaction sites. PmutNgn2 leads to higher reprogramming efficiency and enhances epigenetic remodeling associated with neuronal maturation. However, the differences in binding sites or downstream gene activation cannot fully explain this effect. Instead, we identified Yy1, a transcriptional co-factor recruited by direct interaction with Ngn2 to its target sites. Upon deletion of Yy1, activation of neuronal enhancers, genes and ultimately reprogramming are impaired without affecting Ngn2 binding. Thus, our work highlights the key role of interactors of proneural factors in direct neuronal reprogramming. The molecular mechanisms underlying direct neuronal reprogramming are unclear. Here the authors show Ngn2-mediated chromatin remodeling and its binding sites underlying mouse astrocyte-to-neuron reprogramming and identify Yy1, a transcription co-factor, as an important regulator.

Recent studies provide clues that astrocyte senescence is correlated with Parkinson’s disease (PD) progression, while little is known about the molecular basis for astrocyte senescence in PD. Here, we found that cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) was upregulated in senescent astrocytes of PD and aged mice. Strikingly, deletion of astrocytic cGAS significantly prevented senescence of astrocytes and neurodegeneration. Furthermore, we identified LCN2 as the effector of cGAS-STING signal by RNA-Seq analysis. Genetic manipulation of LCN2 expression proved the regulation of cGAS-STING-LCN2 axis in astrocyte senescence. Additionally, YY1 was discovered as the transcription factor of LCN2 by chromatin immunoprecipitation. Binding of STING to YY1 impedes nuclear translocation of YY1. Herein, we determine the involvement of the cGAS-STING-YY1-LCN2 signaling cascade in the control of astrocyte senescence and PD progression. Together, this work fills the gap in our understanding of astrocyte senescence, and provides potential targets for delaying PD progression.

G protein subunit Gamma 5 (GNG5) has been found to be involved in regulating glioma progression. However, its function and mechanism in glioblastoma (GBM) progression need to be further elucidated. GBM cell proliferation, apoptosis, invasion and stemness were assessed by cell counting kit 8 assay, EdU assay, flow cytometry, transwell assay and sphere formation assay. The mRNA and protein levels of GNG5 and Yin Yang 1 (YY1) were determined by quantitative real-time PCR and western blot (WB). Detection of the glucose consumption, lactate production and ATP/ADP ratios were used to assess cell glycolysis. Besides, Wnt/β-catenin pathway-related protein levels were examined by WB. Mice xenograft model was also constructed to explore GNG5 roles in vivo. GNG5 was highly expressed in GBM, and its silencing inhibited GBM cell proliferation, invasion, stemness and glycolysis, while promoted apoptosis. Transcription factor YY1 could bind to the GNG5 promoter region and induce its expression. GNG5 overexpression reversed the inhibitory effects of YY1 silencing on GBM cell growth, invasion, stemness and glycolysis. YY1/GNG5 axis could activate the Wnt/β-catenin pathway, and Wnt/β-catenin pathway agonists SKL2001 could revert the effects of GNG5 silencing on GBM cell progression. Furthermore, GNG5 facilitated GBM tumor growth by mediating the Wnt/β-catenin pathway. YY1-mediated GNG5 promoted GBM progression through the Wnt/β-catenin pathway.

Metabolic diseases, including obesity, type 2 diabetes, and cardiovascular disorders, are increasingly recognized as chronic inflammatory conditions driven by dysregulated immune-metabolic interactions. Two pivotal regulators of this crosstalk are Raf kinase inhibitor protein (RKIP) and the transcription factor Yin Yang 1 (YY1), which coordinate inflammatory signaling and metabolic stress responses across multiple tissues. RKIP exerts protective, anti-inflammatory effects by antagonizing the MAPK and NF-κB pathways, thereby preserving tissue homeostasis under metabolic stress. In contrast, YY1 acts as a context-dependent transcriptional regulator that promotes inflammatory gene programs, contributes to maladaptive immune cell differentiation, and exacerbates metabolic dysfunction. Notably, RKIP and YY1 are reciprocally regulated: RKIP suppresses YY1 expression via NF-κB inhibition, whereas YY1 represses RKIP transcription through a Snail-dependent feedback loop. In metabolic disease states, this balance is disrupted, RKIP is downregulated, and YY1 is upregulated, leading to heightened immune activation, cytokine production, and tissue damage. Therefore, we propose that RKIP and YY1 represent two opposing yet dynamically coordinated regulators of immunometabolic balance, functioning as a molecular rheostat that determines whether immune responses shift toward inflammation or resolution under metabolic stress. This review synthesizes current insights into the molecular structures, signaling pathways, and tissue-specific functions of RKIP and YY1, emphasizing their interplay in shaping immune responses in metabolic disorders. We further discuss emerging therapeutic approaches aimed at restoring RKIP-YY1 homeostasis to mitigate chronic inflammation and metabolic pathology.

Using microRNA (miRNA) expression array, we identified that miR-7 was deregulated in colorectal cancer (CRC). We studied the biological role and molecular target of miR-7 in CRC. miR-7 was downregulated in six out of seven colon cancer cell lines. Ectopic expression of miR-7 suppressed colon cancer cell proliferation ( P <0.05), induced apoptosis ( P <0.05) and caused cell-cycle arrest in G1 phase ( P <0.05). The tumor suppressive function of miR-7 was further confirmed in nude mice ( P <0.05). The 3′-untranslated region (3′UTR) of Yin Yang 1 ( YY1 ) mRNA contains an evolutionarily conserved miR-7 binding site using in silico searches, luciferase reporter assay and western blot analysis confirmed that miR-7 directly bound to YY1 3′UTR to negatively regulate the protein expression of YY1 in colon cancer cell lines HCT116 and LOVO. Intriguingly, knock-down of YY1 in three colon cancer cell lines (HCT116, LOVO and DLD1) consistently suppressed cell proliferation ( P <0.01) and induced apoptosis ( P <0.01), indicating the opposite functions of miR-7 and YY1 in CRC. Consistent with these data, ectopic expression of YY1 promoted cell growth by increasing proliferation ( P <0.01) and suppressing apoptosis ( P <0.001). The tumorigenic ability of YY1 was further confirmed in vivo in xenograft-nude mouse model ( P <0.01). In addition, pathway analyses revealed that the oncogenic effect by YY1 was associated with inhibiting p53 and modulating its downstream effectors p15, caspase cascades and C-Jun, and activating Wnt signaling pathway through activating β-catenin, anti-apoptotic survivin and fibroblast growth factor 4. Furthermore, multivariate analysis revealed that patients with YY1 protein high expression had a significant decrease in overall survival, and Kaplan–Meier survival curves showed that these patients had significantly shorter survival than others ( P <0.0001). In conclusion, MiR-7 is a novel miRNA with tumor suppressive function in colon cancer by targeting oncogenic YY1 . YY1 promotes colon cancer growth through inhibiting p53 and promoting Wnt signaling pathways and serves as an independent prognostic biomarker for CRC patients.

Targeting self-renewal is an important goal in cancer therapy and recent studies have focused on Notch signalling in the maintenance of stemness of glioma stem cells (GSCs). Understanding cancer-specific Notch regulation would improve specificity of targeting this pathway. In this study, we find that Notch1 activation in GSCs specifically induces expression of the lncRNA, TUG1 . TUG1 coordinately promotes self-renewal by sponging miR-145 in the cytoplasm and recruiting polycomb to repress differentiation genes by locus-specific methylation of histone H3K27 via YY1-binding activity in the nucleus. Furthermore, intravenous treatment with antisense oligonucleotides targeting TUG1 coupled with a drug delivery system induces GSC differentiation and efficiently represses GSC growth in vivo. Our results highlight the importance of the Notch-lncRNA axis in regulating self-renewal of glioma cells and provide a strong rationale for targeting TUG1 as a specific and potent therapeutic approach to eliminate the GSC population. Self-renewal of cancer stem cells can contribute to glioma progression. Here, the authors show that Notch1 activation in glioma stem cells induces expression of the lncRNA TUG1 , which promotes self-renewal through the repression of differentiation genes, and that targeting TUG1 represses glioma growth in vivo .

Pulmonary fibrosis is a chronic, progressive lung disease associated with lung damage and scarring. The pathological mechanism causing pulmonary fibrosis remains unknown. Emerging evidence suggests prominent roles of epithelial–mesenchymal transition (EMT) of alveolar epithelial cells (AECs) in myofibroblast formation and progressive pulmonary fibrosis. Our previous work has demonstrated the regulation of YY1 in idiopathic pulmonary fibrosis and pathogenesis of fibroid lung. However, the specific function of YY1 in AECs during the pathogenesis of pulmonary fibrosis is yet to be determined. Herein, we found the higher level of YY1 in primary fibroblasts than that in primary epithelial cells from the lung of mouse. A549 and BEAS-2B cells, serving as models for type II alveolar pulmonary epithelium in vitro, were used to determine the function of YY1 during EMT of AECs. TGF-β-induced activation of the pro-fibrotic program was applied to determine the role YY1 may play in pro-fibrogenesis of type II alveolar epithelial cells. Upregulation of YY1 was associated with EMT and pro-fibrotic phenotype induced by TGF-β treatment. Targeted knockdown of YY1 abrogated the EMT induction by TGF-β treatment. Enforced expression of YY1 can partly mimic the TGF-β-induced pro-fibrotic change in either A549 cell line or primary alveolar epithelial cells, indicating the induction of YY1 expression may mediate the TGF-β-induced EMT and pro-fibrosis. In addition, the translocation of NF-κB p65 from the cytoplasm to the nucleus was demonstrated in A549 cells after TGF-β treatment and/or YY1 overexpression, suggesting that NF-κB-YY1 signaling pathway regulates pulmonary fibrotic progression in lung epithelial cells. These findings will shed light on the better understanding of mechanisms regulating pro-fibrogenesis in AECs and pathogenesis of lung fibrosis.

The biological role of miR-500a-5p has not yet been reported in the context of colorectal cancer (CRC). Here, we show that miR-500a-5p expression is decreased in CRC tissues compared with adjacent normal tissues. Low miR-500a-5p expression is associated with malignant progression. Moreover, transfection of CRC cells with miR-500a-5p induces G0/G1 cell cycle arrest and inhibits their growth and migration. Mechanistically, miR-500a-5p directly targets HDAC2 and inhibits HDAC2-mediated proliferation in CRC in nude mice. Furthermore, YY1 binds to the promoter of miR-500a-5p and negatively regulates its transcription. Restoration of miR-500a-5p expression is up-regulated via the p300/YY1/HDAC2 complex. Besides, therapeutic delivery of miR-500a-5p significantly suppresses tumour development in a xenograft tumour model and a HDAC2 inhibitor FK228-treated CRC model. Our studies demonstrate that miR-500a-5p functions as a tumour suppressor in CRC by targeting the p300/YY1/HDAC2 axis, which contributes to the development of and provides new potential candidates for CRC therapy. MicroRNA miR-500a-5p has been linked to oncogenesis but its role in colorectal cancer (CRC) is largely unknown. Here, the authors investigate the role of miR-500a-5p in CRC in vitro and in vivo models and find that miR-500a-5p acts as a tumour suppressor in CRC by targeting the p300/YY1/HDAC2 axis.

PurposeLINC01089 is a newly identified lncRNA and rarely reported in human cancers. Our study aimed to investigate its role in lung cancer.MethodsYY1, LINC01089, and miR-301b-3p levels in lung cancer tissues and cells were assessed using qRT-PCR. Bioinformatics analysis and luciferase reporter, ChIP, and RIP assays were carried out for determining the relationships among YY1, LINC01089, miR-301b-3p, and HPGD. Gain- and loss-of-function assays were carried out to confirm the impacts of LINC01089 and HPDG in lung cancer cells. CCK-8 assay was used to assess cell proliferation rate, and Transwell assay was applied to measure cell invasion and migration. An in vivo tumor model was applied for validating the role of LINC01089.ResultsLINC01089 was decreased in lung cancer tissues and cells, and low LINC01089 level predicted a poor clinical outcome. YY1 directly bound to LINC01089 promoter region and inhibited its transcription. LINC01089 knockdown thwarted the proliferation, invasion, and migration capacity of H1299 and A549 cells and aggravated tumor growth. Specifically, LINC01089 functioned as a competing endogenous RNA of miR-301b-3p to modulate HPGD and thereby affected lung cancer progression.ConclusionOur data revealed that LINC01089, directly suppressed by YY1, inhibited lung cancer progression by targeting the miR-301b-3p/HPGD axis.