The FASEB Journal最新文献

{"title":"Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function","authors":"Elin L. Strachan,&nbsp;Eugene T. Dillon,&nbsp;Mairéad Sullivan,&nbsp;Jeffrey C. Glennon,&nbsp;Amandine Peyrel,&nbsp;Jérôme Sarniguet,&nbsp;Kevin Dubois,&nbsp;Benjamin Delprat,&nbsp;Breandán N. Kennedy,&nbsp;Niamh C. O'Sullivan","doi":"10.1096/fj.202403271R","DOIUrl":"https://doi.org/10.1096/fj.202403271R","url":null,"abstract":"<p>Autosomal optic atrophy (AOA) is a form of hereditary optic neuropathy characterized by the irreversible and progressive degermation of the retinal ganglion cells. Most cases of AOA are associated with a single dominant mutation in <i>OPA1</i>, which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in vivo models of OPA1-mediated AOA, including the first developmentally viable vertebrate <i>Opa1</i> knockout (KO). These models allow for the study of <i>Opa1</i> loss in neurons, specifically RGCs. Though survival is significantly reduced in <i>Opa1</i> deficient zebrafish and <i>Drosophila</i>, both models permit the study of viable larvae. Moreover, zebrafish <i>Opa1</i> KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to <i>Opa1</i> loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting <i>Opa1</i>'s highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in <i>Opa1</i> deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. Our findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403271R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Involvement of CSRP1 in Neuroblastoma Differentiation and Apoptosis Impacting Tumor-Suppressive Therapeutic Responses","authors":"Yu-Han Lin,&nbsp;Jyun-Hong Jiang,&nbsp;Hui-Ching Chuang,&nbsp;Chao-Cheng Huang,&nbsp;Wen-Ming Hsu,&nbsp;Min-Tsui Wu,&nbsp;Ting-Ya Chen,&nbsp;Wei-Shiung Lian,&nbsp;Jiin-Haur Chuang","doi":"10.1096/fj.202500403R","DOIUrl":"https://doi.org/10.1096/fj.202500403R","url":null,"abstract":"<p>Neuroblastoma (NB) is a pediatric malignancy from the neural crest, where differentiation plays a key role in prognosis. We investigated cysteine and glycine-rich protein 1 (CSRP1) as a therapeutic target for NB, as it has been linked to differentiation and carcinogenesis in various cancers. Immunohistochemical analysis of archived NB samples showed a significant correlation between CSRP1 expression and differentiation. Ectopic CSRP1 expression in <i>MYCN</i>-amplified BE(2)-M17 cells increased sensitivity to cisplatin, promoted neurite extension, and enhanced differentiation, apoptosis, and chemosensitivity to 13cisRA. Synergistic apoptotic effects were observed with 5-aza-2′-deoxycytidine (DAC) and Poly(I:C) treatments in SK-N-AS cells implanted in xenografts, linked to upregulation of CSRP1, innate immune receptor RIG-I, and caspase-9 activation. CSRP1 expression was significantly higher in mitochondrial DNA-depleted SK-N-AS <i>ρ</i>0 cells, compared to parent SK-N-AS cells. Cisplatin increased CSRP1 expression further in parent cells but not in <i>ρ</i>0 cells. Simultaneous upregulation of caspase-8 was found in both cell types, but increased caspase-9 only in parent cells, suggesting that both intrinsic and extrinsic apoptosis pathways are involved in CSRP1 function depending on the existence of mitochondrial DNA. These findings indicate that CSRP1 is involved in differentiation, determination of apoptosis, and possibly innate immunity in NB, which endows CSRP1 with the potential to enhance the effects of 13cisRA, DAC, and Poly(I:C) in combination therapies for NB.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500403R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering Changes in 3D-Chromatin Structure and Dynamic Gene Expression During Spermatogenesis","authors":"Haoyan Jin,&nbsp;Yuan Ma,&nbsp;Yaru Xie,&nbsp;Nana Wang,&nbsp;Lingkai Zhang,&nbsp;Wenxian Zeng","doi":"10.1096/fj.202402869R","DOIUrl":"https://doi.org/10.1096/fj.202402869R","url":null,"abstract":"<div>\u0000 \u0000 <p>Spermatogonial stem cells (SSCs) have the potential for self-renewal and differentiation, and normal spermatogenesis maintains a stable number of spermatogonial stem cells and spermatozoa. Spermatogenesis is accompanied by changes in the three-dimensional structure of chromatin and gene expression, but the structural differences between the stages and the higher-order chromatin dynamics have not yet been elucidated. Consequently, we conducted a high-throughput analysis of the chromatin structural organization and gene expression by using porcine spermatogonia (SPG), spermatocytes (SPY) and round spermatids (RS). We found that during spermatogenesis, SPY showed a weaker pattern of chromosomal interactions, attenuated compartmentalisation, and a reduction in the number of TADs (topological associating domains), which was restored during the subsequent period of round spermatids. These findings suggest reprogramming of higher-order chromatin structures during porcine spermatogonia differentiation. Our results reveal that chromatin structure changes during porcine spermatogenesis, along with changes in gene expression. In conclusion, our study reveals the interrelationships between higher-order chromatin structure and gene expression in spermatogonia, spermatocytes, and round spermatids, providing new insights into the understanding of spermatogenesis as well as basic theoretical data for male reproductive techniques in biological sciences.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated Linoleic Acid Intake Becomes a Risk Factor for Polycystic Ovary Syndrome by Affecting Ovarian Granulosa Cells","authors":"Wenying Zhang,&nbsp;Fuju Wu","doi":"10.1096/fj.202402648RR","DOIUrl":"https://doi.org/10.1096/fj.202402648RR","url":null,"abstract":"<p>Polycystic ovary syndrome (PCOS) is one of the most common endocrine and metabolic disorders in females of reproductive age; this condition is particularly concerning due to its potential to cause infertility. Linoleic acid (LA) is an essential and widely consumed <i>n</i>−6 polyunsaturated fatty acid. In the past decades, LA intake has sharply surged, as recommended by dietary guidelines and advances in the food industry. An increasing number of people are questioning the health benefits of LA. In patients with PCOS, dietary management is crucial for improving symptoms to obtain good outcomes with assisted reproductive technology (ART). Diets rich in <i>n</i>−6 fatty acid has become “arch-criminal” of “silent inflammation.” PCOS is also associated with low-grade chronic inflammation. Therefore, identification of the relationship between dietary LA and PCOS is urgently required. In this study, we first conducted experiments to observe the effects of different LA concentrations on PCOS-related phenotypes in mice. The results showed that medium and high concentrations of LA led to PCOS-like changes in mice, presenting with disordered estrous cycles, polycystic ovaries, and hyperandrogenism. LA is independent of PCOS-related weight gain and insulin resistance. LA caused systemic inflammation, reduced antioxidant capacity, and increased ovary apoptosis in mice. To explore how LA acts in vivo, we used the ovarian granulosa cell line KGN to detect alterations in the levels of granulosa cells (GCs). In addition to having no impact on endocrine function, LA can decrease the antioxidant capacity, reduce mitochondrial function, increase the apoptotic rate, and induce inflammation in GCs. To obtain more information, the pretreated GCs were subjected to transcriptome sequencing. The abundant RNA-Seq results make future directions for understanding the mechanism of LA action on GCs in PCOS more explicit. In summary, elevated LA intake is a risk factor for PCOS that affects ovarian GCs. Further studies should focus on establishing a strict intake range for the prevention and treatment of PCOS.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402648RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION: Effect of Mechanical Tension on Fibroblast Transcriptome Profile and Regulatory Mechanisms of Myocardial Collagen Turnover","authors":"","doi":"10.1096/fj.70513","DOIUrl":"https://doi.org/10.1096/fj.70513","url":null,"abstract":"<div>\u0000 \u0000 <p><b>RETRACTION:</b> M. Shiraishi, K. Suzuki, and A. Yamaguchi, “Effect of Mechanical Tension on Fibroblast Transcriptome Profile and Regulatory Mechanisms of Myocardial Collagen Turnover,” <i>FASEB Journal</i> 37, no. 4 (2023): e22841. https://doi.org/10.1096/fj.202201899R.</p>\u0000 <p>The above article, published online on 01 March 2023, in Wiley Online Library (wileyonlinelibrary.com), and its erratum (https://doi.org/10.1096/fj.202301989), have been retracted by agreement between the authors; the journal Editor-in-Chief, Dr. Loren E. Wold, the Federation of American Societies for Experimental Biology, and Wiley Periodicals LLC. This retraction follows a previous erratum to correct image duplications in Figures 2 and 3 as well as Supplementary Figures 1, 3, and 5. The authors contacted the journal and requested retraction of their article following an investigation by Jichi Medical University, which has concluded that there was a lack of primary research data and corroborating evidence which could confirm the source of the errors and whether the experiments had been performed as described. The retraction was agreed to because the investigation performed by the university confirmed a lack of evidence to support the published erratum, and as such the errors in the article fundamentally compromise the editor's confidence in the conclusions presented.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.70513","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SETDB1 recruits CBX3 to regulate the SIRT4/PTEN axis, inhibiting autophagy and promoting ischemia–reperfusion-induced kidney injury","authors":"Yuan-Fei Liu,&nbsp;Fan Li,&nbsp;Cheng-Yun Xu,&nbsp;Yan Chen,&nbsp;Wei-Ping Tu,&nbsp;Chong Huang","doi":"10.1096/fj.202403024R","DOIUrl":"https://doi.org/10.1096/fj.202403024R","url":null,"abstract":"<p>Ischemia–reperfusion (I/R) injury is a significant factor in the development of acute kidney injury (AKI), particularly in clinical scenarios, such as kidney transplantation, cardiac surgery, and severe hypotension. Autophagy, a critical process that eliminates damaged cellular components, has been shown to mitigate I/R injury by reducing oxidative stress and enhancing cell survival. However, when autophagy is disrupted, it can exacerbate kidney damage. Elucidating the role of autophagy in I/R injury is essential for uncovering the molecular mechanisms driving AKI and could facilitate the development of autophagy-based therapies. Protein expression levels were analyzed through western blot, immunohistochemistry (IHC), and immunofluorescence (IF) staining techniques. Interactions between SIRT4, SETDB1, and CBX3 were explored using chromatin immunoprecipitation (ChIP), sequential ChIP (ChIP-reChIP), and co-immunoprecipitation (Co-IP) assays. The association between SIRT4 and PTEN was also examined via Co-IP. Transmission electron microscopy (TEM) was employed to visualize autophagosomes. Furthermore, an in vivo rat model of I/R injury was developed for validation of the findings. Sirtuin 4 (SIRT4) expression was reduced, and autophagy was impaired during I/R injury. Moreover, SIRT4 interacted with phosphatase and tensin homolog (PTEN) to regulate its expression. Furthermore, SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) mediated histone H3 lysine 9 trimethylation (H3K9me3) modifications and recruited chromobox protein homolog 3 (CBX3) to the SIRT4 promoter, leading to the repression of SIRT4 expression in kidney proximal tubular cells. Importantly, SETDB1 knockdown upregulated SIRT4, decreased PTEN expression, promoted autophagy, and protected rats against I/R injury in vivo. SETDB1 recruits CBX3 to regulate the SIRT4/PTEN axis, inhibiting autophagy and promoting I/R-induced kidney injury. These results suggest that targeting the SETDB1-SIRT4 axis could offer a novel therapeutic strategy to mitigate renal damage in I/R-induced AKI.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early Growth Response 1 Plays an Essential Role in Proinflammatory and Osteoclastogenic Activities of Lipopolysaccharide-Stimulated Osteoblasts","authors":"Miyoko Yutoku,&nbsp;Kosuke Fujita,&nbsp;Norika Chiba,&nbsp;Ryohei Tada,&nbsp;Tomokazu Ohnishi,&nbsp;Mitsutaka Sugimura,&nbsp;Tetsuya Matsuguchi","doi":"10.1096/fj.202402623R","DOIUrl":"https://doi.org/10.1096/fj.202402623R","url":null,"abstract":"<div>\u0000 \u0000 <p>Lipopolysaccharide (LPS) of Gram-negative bacteria in oral plaque is the major cause of periodontal disease. It is involved in the induction of inflammation and alveolar bone resorption at least partly by directly reacting to Toll-like receptor (TLR) 4 on osteoblasts. LPS induces osteoblasts to express proinflammatory cytokines, chemokines, and prostaglandins, as well as macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL), which directly activate adjacent osteoclasts toward bone resorption. However, the regulator mechanisms have not been fully revealed at the molecular level. Here, we have demonstrated that LPS rapidly induces expression of early growth response 1 (EGR1), a zinc-finger transcription factor, and analyzed its physiological functions in osteoblasts. In both primary osteoblasts and an osteoblast cell line, LPS induced expression of EGR1 mRNA and protein within 30 min and 60 min, respectively, which were relatively slower than in macrophages. Inhibition of EGR1 by siRNA significantly inhibited LPS-induced mRNA expression of the tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokines, cyclooxygenase-2 (COX2), matrix metalloproteinase-13 (MMP13), M-CSF, and RANKL in osteoblasts. Moreover, forced overexpression of EGR1 by the inducible expression system was sufficient to increase mRNA expression levels of TNF, IL-6, COX2, MMP13, and RANKL without LPS stimulation. As for the intracellular signal transduction, LPS-induced EGR1 expression in osteoblasts was dependent on the unique c-Jun N-terminal kinase (JNK)–extracellular signal-regulated kinase (ERK) activation pathway. Our data suggest an essential role of EGR1 in osteoblast responses to LPS-inducing tissue inflammation and osteolysis, providing new insights into the pathogenesis of periodontal disease.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-29 inhibits endothelial-to-mesenchymal transition in pulmonary hypertension of the newborn by regulating LRP6","authors":"Yingjie Wang,&nbsp;Le Sun,&nbsp;Xianxian Jia,&nbsp;Miao Yang,&nbsp;Wei Xu","doi":"10.1096/fj.202401069RRR","DOIUrl":"https://doi.org/10.1096/fj.202401069RRR","url":null,"abstract":"<p>Pulmonary hypertension of the newborn (PHN) is a common pulmonary vascular disease in newborns, affecting the prognosis of affected infants and even leading to death. Currently, there is still no specific targeted prevention and treatment program available. In recent years, research on the regulatory mechanism of endothelial-to-mesenchymal transition (EndMT) has become a hot topic, with the interplay between miRNAs and the Wnt signaling pathway playing an important role. MiR-29 is highly expressed in distal pulmonary arteriolar smooth muscle cells and endothelial cells. In miR-29 gene knockout mice, pathological changes in lung tissue can be observed, indicating an obstruction in the maturation of smooth muscle cells in the distal pulmonary arterioles. LRP6 is an important Wnt co-receptor in the Wnt signaling pathway, and the Targetscan website predicts a binding site between miR-29 and LRP6. Therefore, our studies establish a role for decreased miR29a in the endothelial mesenchymal transition through activation of the LRP6-Wnt signaling pathway in neonatal hypoxia-mediated PAH. By generating hypoxic newborn rat models of pulmonary artery hypertension and hypoxic injury models of pulmonary vascular endothelial cells, we observed the presence of EndMT in the model group, as well as the activation of the LRP6 and Wnt/β-catenin signaling pathways and the differential expression of the miR-29 family, particularly miR-29a. Subsequently, We used cell transfection technology to overexpress/knock down miR-29a and LRP6, respectively, to observe changes in EndMT-related indicators and successfully found that miR-29a and LRP6 can negatively and positively regulate the occurrence of EndMT, respectively. Finally, the dual-luciferase reporter gene assay confirmed that LRP6 can directly bind to miR-29a-3p. These findings provide experimental evidence of the potential of miR-29 as a novel target for the prevention and treatment of PHN.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STING Facilitates Vascular Calcification via p-STAT1/NLRP3 Signal","authors":"Lihe Lu,&nbsp;Xiaoyu Liu,&nbsp;Yuan Gong,&nbsp;Xingchen Zhou,&nbsp;An Chen,&nbsp;Mingxi Li,&nbsp;Liyun Feng,&nbsp;Zirong Lan,&nbsp;Yuanzhi Ye,&nbsp;Qingchun Liang,&nbsp;Jianyun Yan","doi":"10.1096/fj.202403334R","DOIUrl":"https://doi.org/10.1096/fj.202403334R","url":null,"abstract":"<div>\u0000 \u0000 <p>Vascular calcification is an independent predictor of cardiovascular mortality in patients with chronic kidney disease (CKD), yet no approved treatment exists. The cGAS-STING signaling participates in various cardiovascular diseases. Notably, DNA damage, an important regulator of vascular calcification, activates the cGAS-STING signaling. However, it remains poorly understood whether STING regulates vascular calcification under CKD conditions. In the current study, we showed that the expression of STING was elevated during vascular calcification. STING knockdown or pharmacological inhibition decreased calcium deposits in vascular smooth muscle cells and human arterial rings, while its activation exacerbated calcification. Furthermore, STING knockout mice exhibited reduced aortic calcification. RNA sequencing analysis suggested that the STAT1 signaling pathway may mediate STING-induced vascular calcification. STING knockdown decreased phosphorylated STAT1 (p-STAT1) levels, and inhibition of p-STAT1 mitigated STING-induced calcification in VSMCs and human arterial tissues. Additionally, STING knockdown downregulated NLRP3 expression, and inhibiting NLRP3 further attenuated STING-induced VSMC calcification, indicating STING accelerates vascular calcification via NLRP3 activation. Altogether, our study highlights the STING/p-STAT1/NLRP3 signaling axis as a key mediator in vascular calcification, suggesting that targeting STING may represent a promising therapeutic approach for vascular calcification in CKD patients.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143786884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TCF19/CDKN2A Regulates Glycolysis and Macrophage M2 Polarization for Osteosarcoma Progression","authors":"Xinyue Hu,&nbsp;Wei Chen,&nbsp;Kaiyuan Yang,&nbsp;Chunhui Zhu,&nbsp;Zhuang Li,&nbsp;Dong Zheng,&nbsp;Rui Geng","doi":"10.1096/fj.202401343RRR","DOIUrl":"https://doi.org/10.1096/fj.202401343RRR","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteosarcoma (OS) is the most common malignant tumor of the bone. This paper aimed to explore the mechanism of macrophage polarization and glycolysis in OS. Gene expression microarray GSE42572 for OS was downloaded from the GEO database and validated in TCGA-SARC. CDKN2A expression in OS cell lines and normal human bone osteoblasts was detected. Saos2 cells were transfected with siRNA-CDKN2A, and U2OS were transfected with pcDNA3.4-CDKN2A to knock down or upregulate CDKN2A expression to explore the role in malignant behaviors. Extracellular acidification rate, oxygen consumption rate, and glycolysis-related proteins were detected. Saos2 cells were co-incubated with THP-1 cells, and CD206 and CD86 levels were detected. The secretion of IL-10 and IL-12 by macrophages was measured. CDKN2A upstream regulatory elements were predicted by online databases, and the binding of TCF19 to the CDKN2A promoter was validated. Xenograft OS was established to verify the effect of TCF19 knockdown on OS growth in mice. CDKN2A was highly expressed in OS tissues and cell lines. CDKN2A knockdown inhibited the proliferation, migration, and invasion of Saos2 cells and promoted apoptosis and glycolysis. After CDKN2A knockdown in Saos2 cells and co-incubation with macrophages, CD206-positive cells decreased, CD86-positive cells increased, IL-10 decreased, and IL-12 increased. TCF19 was enriched on the CDKN2A promoter and promoted CDKN2A expression. Upregulation of CDKN2A by TCF19 promoted glycolysis and M2 polarization. TCF19 downregulation inhibited OS growth, metabolic reprogramming, and CDKN2A expression in OS mice. TCF19 is enriched in the CDKN2A promoter and enhances its expression, which in turn activates glycolysis and M2 polarization, ultimately promoting OS progression.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}