Experimental and Molecular Medicine最新文献

{"title":"NR4A1 suppresses breast cancer growth by repressing c-Fos-mediated lipid and redox dyshomeostasis.","authors":"Cen Jiang, Youzhi Zhu, Junsi Zhang, Huaying Chen, Weiwei Li, Ruiwang Xie, Lingjun Kong, Ling Chen, Xiangjin Chen, Huifang Huang, Sunwang Xu","doi":"10.1038/s12276-025-01430-3","DOIUrl":"https://doi.org/10.1038/s12276-025-01430-3","url":null,"abstract":"<p><p>The specific function of NR4A1 as a transcriptional regulator in cancer remains unclear. Here we report the biological effect of NR4A1 in suppressing breast cancer (BC) growth. We found that NR4A1 deficiency was correlated with BC progression in the clinic. Genetic deletion of NR4A1 in BC cells significantly promoted cellular proliferation and tumor growth. Moreover, global metabolome screening indicated that the deletion of NR4A1 resulted in tumor lipid remodeling and phospholipid accumulation, which was accompanied by increases in fatty acid and lipid uptake. In addition, NR4A1 knockout induced oxidative stress that aggravated redox balance disruption. Mechanistically, transcriptomic and epigenomic analyses revealed that NR4A1 restrained BC cell proliferation by directly interacting with c-Fos and competitively inhibiting c-Fos binding to the promoter of the target gene PRDX6, which is involved in lipid and redox homeostasis. Notably, we confirmed that the treatment of BC cells with the selective NR4A1 agonist cytosporone B significantly activated the expression of NR4A1, followed by increased interaction between NR4A1 and c-Fos, thereby interfering with c-Fos-mediated transcriptional regulation of BC cell growth. Thus, NR4A1 plays a vital role in reducing the c-Fos-induced activation of downstream signaling cascades in BC, suggesting that agents that activate NR4A1 may be potential therapeutic strategies.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Correction: Crosstalk between FTH1 and PYCR1 dysregulates proline metabolism and mediates cell growth in KRAS-mutant pancreatic cancer cells","authors":"Ji Min Park,&nbsp;Yen-Hao Su,&nbsp;Chi-Shuan Fan,&nbsp;Hsin-Hua Chen,&nbsp;Yuan-Kai Qiu,&nbsp;Li-Li Chen,&nbsp;Hsin-An Chen,&nbsp;Thamil Selvee Ramasamy,&nbsp;Jung-Su Chang,&nbsp;Shih-Yi Huang,&nbsp;Wun-Shaing Wayne Chang,&nbsp;Alan Yueh-Luen Lee,&nbsp;Tze-Sing Huang,&nbsp;Cheng-Chin Kuo,&nbsp;Ching-Feng Chiu","doi":"10.1038/s12276-025-01437-w","DOIUrl":"10.1038/s12276-025-01437-w","url":null,"abstract":"","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 3","pages":"700-701"},"PeriodicalIF":9.5,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01437-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein lactylation in cancer: mechanisms and potential therapeutic implications","authors":"Hyunsoo Rho,&nbsp;Nissim Hay","doi":"10.1038/s12276-025-01410-7","DOIUrl":"10.1038/s12276-025-01410-7","url":null,"abstract":"Increased glycolysis, which leads to high lactate production, is a common feature of cancer cells. Recent evidence suggests that lactate plays a role in the post-translational modification of histone and nonhistone proteins via lactylation. In contrast to genetic mutations, lactylation in cancer cells is reversible. Thus, reversing lactylation can be exploited as a pharmacological intervention for various cancers. Here we discuss recent advances in histone and nonhistone lactylation in cancer, including l-, d- and s-lactylation, as well as alanyl-tRNA synthetase as a novel lactyltransferase. We also discuss potential approaches for targeting lactylation as a therapeutic opportunity in cancer treatment. In the 1920s, Otto Warburg discovered that cancer cells use a lot of sugar even when oxygen is present. This process, called aerobic glycolysis, produces a substance called lactate. Scientists used to think lactate was just waste, but recent studies show it has important roles in cancer. Researchers found that lactate can change proteins in cells through a process called lactylation, which affects how genes are turned on or off. In this study, the authors explored how lactylation impacts cancer. They used various methods to study proteins and genes in cancer cells. They found that lactylation can change both histone proteins and nonhistone proteins, affecting gene expression and protein stability. This process can help cancer cells grow and resist treatment. The researchers concluded that targeting lactylation could be a new way to treat cancer. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 3","pages":"545-553"},"PeriodicalIF":9.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01410-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Orchestrating epigenetics: a comprehensive review of the methyltransferase SETD6","authors":"Anand Chopra,&nbsp;Michal Feldman,&nbsp;Dan Levy","doi":"10.1038/s12276-025-01423-2","DOIUrl":"10.1038/s12276-025-01423-2","url":null,"abstract":"Transcription is regulated by an intricate and extensive network of regulatory factors that impinge upon target genes. This process involves crosstalk between a plethora of factors that include chromatin structure, transcription factors and posttranslational modifications (PTMs). Among PTMs, lysine methylation has emerged as a key transcription regulatory PTM that occurs on histone and non-histone proteins, and several enzymatic regulators of lysine methylation are attractive targets for disease intervention. SET domain-containing protein 6 (SETD6) is a mono-methyltransferase that promotes the methylation of multiple transcription factors and other proteins involved in the regulation of gene expression programs. Many of these SETD6 substrates, such as the canonical SETD6 substrate RELA, are linked to cellular pathways that are highly relevant to human health and disease. Furthermore, SETD6 regulates numerous cancerous phenotypes and guards cancer cells from apoptosis. In the past 15 years, our knowledge of SETD6 substrate methylation and the biological roles of this enzyme has grown immensely. Here we provide a comprehensive overview of SETD6 that will enhance our understanding of this enzyme’s role in chromatin and in selective transcriptional control, the contextual biological roles of this enzyme, and the molecular mechanisms and pathways in which SETD6 is involved, and we highlight the major trends in the SETD6 field. The chemical modification of proteins, such as lysine methylation, influences their role in the cell. This review focuses on an epigenetic enzyme called SETD6 that adds small chemical methyl groups to certain proteins. Over the past 15 years, research on SETD6 has shown that it plays an important role in human health and disease. The interactions of SETD6 with other proteins, particularly its ability to chemically modify them, have been shown to influence the individual functions of these proteins. This influence affects cells at the epigenetic level—affecting gene regulation—as well as cell behavior. Whether SETD6 promotes or suppresses cancerous properties depends on the type of cancer. Therefore, research focusing on the role of SETD6 in the cell is crucial to understand whether SETD6 could be a promising target for therapeutic intervention. .","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 3","pages":"533-544"},"PeriodicalIF":9.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01423-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of hypoimmunogenic universal iPS cells through HLA-type gene knockout","authors":"Juryun Kim,&nbsp;Yoojun Nam,&nbsp;Doyeong Jeon,&nbsp;Yujin Choi,&nbsp;SeonJu Choi,&nbsp;Chang Pyo Hong,&nbsp;Siyoung Kim,&nbsp;Hyerin Jung,&nbsp;Narae Park,&nbsp;Yeowon Sohn,&nbsp;Yeri Alice Rim,&nbsp;Ji Hyeon Ju","doi":"10.1038/s12276-025-01422-3","DOIUrl":"10.1038/s12276-025-01422-3","url":null,"abstract":"Hypoimmunogenic universal induced pluripotent stemn (iPS) cells were generated through the targeted disruption of key genes, including human leukocyte antigen (HLA)-A, HLA-B and HLA-DR alpha (DRA), using the CRISPR–Cas9 system. This approach aimed to minimize immune recognition and enhance the potential of iPS cells for allogeneic therapy. Heterozygous iPS cells were used for guide RNA design and validation to facilitate the knockout (KO) of the HLA-A, HLA-B and HLA-DRA genes. The electroporation of iPS cells using the selected guide RNAs enabled the generation of triple-KO iPS cells, followed by single-cell cloning for clone selection. Clone A7, an iPS cell with targeted KOs of the HLA-A, HLA-B and HLA-DRA genes, was identified as the final candidate. Messenger RNA analysis revealed robust expression of pluripotency markers, such as octamer-binding transcription factor 4, sex-determining region Y box 2, Krüppel-like factor 4, Lin-28 homolog A and Nanog homeobox, while protein expression assays confirmed the presence of octamer-binding transcription factor 4, stage-specific embryonic antigen 4, Nanog homeobox and tumor rejection antigen 1–60. A karyotype examination revealed no anomalies, and three-germ layer differentiation assays confirmed the differentiation potential. After interferon gamma stimulation, the gene-corrected clone A7 lacked HLA-A, HLA-B and HLA-DR protein expression. Immunogenicity testing further confirmed the hypoimmunogenicity of clone A7, which was evidenced by the absence of proliferation in central memory T cells and effector memory T cells. In conclusion, clone A7, a triple-KO iPS cell clone that demonstrates immune evasion properties, retained its intrinsic iPS cell characteristics and exhibited no immunogenicity. This study focuses on improving cell therapy by reducing the immune response to induced pluripotent stem (iPS) cells. Researchers aimed to generate iPS cells that are less likely to be rejected by the immune system by editing specific genes. The team used a tool called CRISPR–Cas9 to remove certain genes, known as HLA-A, HLA-B and HLA-DRA, from iPS cells. By removing these genes, researchers hoped to make the iPS cells less recognizable to the immune system. The study found that the edited iPS cells did not trigger a strong immune response in lab tests. The edited cells maintained their ability to differentiate into various cell types and showed reduced signs of being attacked by immune cells. This research suggests that editing specific genes in iPS cells can make them more suitable for use in therapies without being rejected by the body. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 3","pages":"686-699"},"PeriodicalIF":9.5,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01422-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA Gm35585 transcriptionally activates the peroxidase EHHADH against diet-induced fatty liver","authors":"Ming Jin,&nbsp;Qian Lu,&nbsp;Ninglin Xia,&nbsp;Xue Fan,&nbsp;Ziling Zhang,&nbsp;Xiaofei Huang,&nbsp;Li Sun,&nbsp;Luyong Zhang,&nbsp;Zhenzhou Jiang,&nbsp;Qinwei Yu","doi":"10.1038/s12276-025-01420-5","DOIUrl":"10.1038/s12276-025-01420-5","url":null,"abstract":"Metabolic-dysfunction-associated steatotic liver disease is one of the most common chronic liver diseases worldwide and has no approved treatment thus far. Here we report that the hepatic overexpression of Gm35585, a novel lncRNA downregulated in the livers of mice fed a high-fat diet, is functionally important in alleviating hepatic lipid accumulation pathologies. Gm35585 activates the peroxisome proliferator-activated receptor α (PPARα) signaling pathway and promotes the expression of downstream PPARα-target gene, enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase (EHHADH), which is one of the four enzymes of the peroxisomal β-oxidation pathway. Activation of EHHADH promotes the oxidation of long-chain fatty acids (LCFAs), and the increased levels of hepatic LCFAs contribute to metabolic-dysfunction-associated steatotic liver disease. Mechanistically, Gm35585 binds to retinoid X receptor α (RXRα) and then forms a PPARα/RXRα heterodimer with PPARα and guides the heterodimer to recognize the promoter of EHHADH, which is called peroxisome proliferator-activated receptor response element, causing transcriptional activation of EHHADH. Taken together, Gm35585 is a hepatic lipid metabolism regulator that activates EHHADH transcription, promoting peroxisomal β-oxidation of LCFAs and ultimately ameliorating diet-induced fatty liver. Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a growing global health issue affecting millions and leads to severe liver conditions. Researchers explored new ways to treat MASLD by studying a molecule called Gm35585. In their study, they used mice fed a high-fat diet to mimic human liver disease. They found that Gm35585 helps to break down harmful fats in the liver by activating a protein called EHHADH, which is involved in fat metabolism. This process reduces fat accumulation in the liver, potentially slowing disease progression. They concluded that Gm35585 could be a promising target for developing new MASLD treatments. Their findings suggest that enhancing the activity of EHHADH through Gm35585 might offer a new therapeutic strategy. Future research could focus on how this approach can be applied to human treatments for fatty liver disease. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 3","pages":"652-666"},"PeriodicalIF":9.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01420-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VGF and the VGF-derived peptide AQEE30 stimulate osteoblastic bone formation through the C3a receptor","authors":"Sung-Ah Moon,&nbsp;Jin-Man Kim,&nbsp;Young-Sun Lee,&nbsp;Han Jin Cho,&nbsp;Young Jin Choi,&nbsp;Jong Hyuk Yoon,&nbsp;Dayea Kim,&nbsp;Xiangguo Che,&nbsp;Xian Jin,&nbsp;In-Jeoung Baek,&nbsp;Seung Hun Lee,&nbsp;Je-Young Choi,&nbsp;Jung-Min Koh","doi":"10.1038/s12276-025-01419-y","DOIUrl":"10.1038/s12276-025-01419-y","url":null,"abstract":"New therapeutic targets, especially those that stimulate bone formation in cortical bone, are needed to overcome the limitations of current antiosteoporotic drugs. We previously demonstrated that factors secreted from megakaryocytes (MKs) promote bone formation. Here we conducted a proteomic analysis to identify a novel bone-forming factor from MK secretions. We revealed that Vgf, a nerve growth factor-responsive gene, and its derived active peptide AQEE30 in MK-conditioned medium play important roles in osteoblast proliferation and in vitro bone formation. In both Vgf-deficient male and female mice, the cortical bone mass was significantly decreased due to reductions in osteoblast number and bone formation activity. AQEE30 stimulated intracellular cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in osteoblasts, whereas an adenylyl cyclase inhibitor blocked AQEE30-stimulated osteoblast proliferation and in vitro bone formation. Complement C3a receptor-1 (C3AR1) was expressed and interacted with AQEE30 in osteoblasts, and C3AR1 inhibition blocked all AQEE30-induced changes, including stimulated proliferation, bone formation and cAMP production, in osteoblasts. Injecting mini-PEGylated AQEE30 into calvaria increased the number of osteocalcin-positive cells and new bone formation. In conclusion, this study reveals a novel role of VGF in bone formation, particularly in cortical bone, and shows that AQEE30, a VGF-derived peptide, mediates this role by activating cAMP–PKA signaling via the C3AR1 receptor in osteoblasts. Osteoporosis is a common bone disease that weakens bones and increases fracture risk. Current treatments have limitations, especially in preventing nonvertebral fractures. Researchers focused on a protein called VGF, which is known for its role in the brain but not in bone health. The study used mice and cell cultures to investigate VGF’s effects on bones. They found that VGF and its peptide AQEE30 promote bone formation by stimulating osteoblasts. They used mass spectrometry to discover that VGF is important for bone health. Mice lacking VGF had weaker bones, especially in the cortical (outer) layer. The study showed that AQEE30 works by increasing cAMP levels, a molecule that helps cells communicate and grow. This discovery suggests that targeting VGF and AQEE30 could lead to new treatments for osteoporosis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 3","pages":"637-651"},"PeriodicalIF":9.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01419-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"KLF6-mediated recruitment of the p300 complex enhances H3K23su and cooperatively upregulates SEMA3C with FOSL2 to drive 5-FU resistance in colon cancer cells","authors":"Bishu Zhang,&nbsp;Tuoya Qi,&nbsp;Jiewei Lin,&nbsp;Shuyu Zhai,&nbsp;Xuelong Wang,&nbsp;Leqi Zhou,&nbsp;Xiaxing Deng","doi":"10.1038/s12276-025-01424-1","DOIUrl":"10.1038/s12276-025-01424-1","url":null,"abstract":"Histone lysine succinylation, an emerging epigenetic marker, has been implicated in diverse cellular functions, yet its role in cancer drug resistance is not well understood. Here we investigated the genome-wide alterations in histone 3 lysine 23 succinylation (H3K23su) and its impact on gene expression in 5-fluorouracil (5-FU)-resistant HCT15 colon cancer cells. We utilized CUT&amp;Tag assays to identify differentially enriched regions (DERs) of H3K23su in 5-FU-resistant HCT15 cells via integration with ATAC-seq and RNA sequencing data. The regulatory network involving transcription factors (TFs), notably FOSL2 and KLF6, and their downstream target genes was dissected using motif enrichment analysis and chromatin immunoprecipitation assays. Our results revealed a strong positive correlation between H3K23su DERs, differentially expressed genes (DEGs) and H3K27ac, indicating that H3K23su enrichment is closely related to gene activation. The DEGs associated with the H3K23su GAIN regions were significantly enriched in pathways related to colorectal cancer, including the Wnt, MAPK and p53 signaling pathways. FOSL2 and KLF6 emerged as pivotal TFs potentially modulating DEGs associated with H3K23su DERs and were found to be essential for sustaining 5-FU resistance. Notably, we discovered that FOSL2 and KLF6 recruit the PCAF–p300/CBP complex to synergistically regulate SEMA3C expression, which subsequently modulates the canonical Wnt–β-catenin signaling pathway, leading to the upregulation of MYC and FOSL2. This study demonstrated that H3K23su is a critical epigenetic determinant of 5-FU resistance in colon cancer cells, exerting its effects through the modulation of critical genes and TFs. These findings indicate that interventions aimed at targeting TFs or enzymes involved in H3K23su modification could represent potential therapeutic strategies for treating colorectal cancers that are resistant to 5-FU treatment. Colon cancer is a major health concern worldwide, with treatments such as chemotherapy often facing challenges due to drug resistance. This study explores why colon cancer cells become resistant to the common chemotherapy drug 5-fluorouracil. The researchers focused on a process called lysine succinylation and its role in drug resistance. Using advanced techniques such as CUT&amp;Tag (a method to study protein–DNA interactions), they examined changes in specific proteins in colon cancer cells resistant to 5-fluorouracil. They found that certain proteins, including FOSL2 and KLF6, help to maintain this resistance by affecting gene expression through pathways such as Wnt–β-catenin. The study concludes that targeting these proteins and pathways could help to overcome drug resistance in colon cancer. Future research may focus on developing new treatments that disrupt these processes, potentially improving outcomes for patients with resistant colon cancer. This summary was initially drafted using artificial intelligence, then revised and fact-chec","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 3","pages":"667-685"},"PeriodicalIF":9.5,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01424-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143626050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"sLZIP functions as a key modulator of bone remodeling by regulating the crosstalk between osteoblasts and osteoclasts","authors":"Sungyeon Park,&nbsp;Jeonghan Kim,&nbsp;Jesang Ko","doi":"10.1038/s12276-025-01414-3","DOIUrl":"10.1038/s12276-025-01414-3","url":null,"abstract":"Human small leucine zipper protein (sLZIP) regulates the differentiation of both osteoblasts (OBs) and osteoclasts (OCs). However, the regulatory role of sLZIP in bone remodeling and its involvement in bone disorders remain unclear. Here we investigated the role of sLZIP in bone remodeling and its importance in the development of cell therapies for bone diseases. sLZIP increased bone mass in an osteoporosis mouse model. Moreover, bone mass was lower in mesenchymal stem cell-specific murine LZIP-1/2 knockout (Osx-LZIP-1/2fl/fl) mice than in control LZIP-1/2fl/fl mice. Compared with control mice, Osx-LZIP-1/2fl/fl mice presented delayed bone fracture healing in osteoporosis. Conditioned medium from OBs differentiated from adipose-derived stem cells from Osx-LZIP-1/2fl/fl mice attenuated OC formation and the migration of bone marrow-derived macrophages. However, conditioned medium from OCs from sLZIP transgenic mice induced OB differentiation and migration. sLZIP regulates the secretion of OC-derived sphingosine-1-phosphate, which induces OB differentiation. sLZIP also regulates OB-derived WNT16, which inhibits OC differentiation. Therefore, sLZIP is a key modulator of the crosstalk between OBs and OCs and promotes bone remodeling and fracture healing in osteoporosis. In addition, sLZIP-overexpressing adipose-derived stem cells promote bone formation and repair in osteoporosis. sLZIP is an excellent target for stem cell-based treatment of osteoporosis. Bone remodeling is a natural process where old bone is replaced with new bone. This process can become imbalanced, leading to diseases such as osteoporosis. This study explores the role of sLZIP in bone health. Researchers used mice to study how sLZIP affects bone formation and healing. They found that sLZIP helps in forming new bone and aids in healing fractures. The study involved creating bone defects in mice and observing the effects of sLZIP on bone repair. Using various laboratory techniques to measure bone density and structure, the authors show that sLZIP promotes bone growth and helps repair fractures by enhancing communication between cells that build bone and those that break it down. The researchers conclude that sLZIP could be a promising target for developing new treatments for osteoporosis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 3","pages":"601-615"},"PeriodicalIF":9.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01414-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the mechanism of proanthocyanidins in central analgesia: redox regulation and KCNK3 blockade","authors":"Junxiang Gu,&nbsp;Jian Wang,&nbsp;Hongwei Fan,&nbsp;Yi Wei,&nbsp;Yan Li,&nbsp;Chengwen Ma,&nbsp;Keke Xing,&nbsp;Pan Wang,&nbsp;Zhenyu Wu,&nbsp;Teng Wu,&nbsp;Xiaoyi Li,&nbsp;Luoying Zhang,&nbsp;Yunyun Han,&nbsp;Tao Chen,&nbsp;Jianqiang Qu,&nbsp;Xianxia Yan","doi":"10.1038/s12276-025-01412-5","DOIUrl":"10.1038/s12276-025-01412-5","url":null,"abstract":"Neuropathic pain causes enduring physical discomfort and emotional distress. Conventional pharmacological treatments often provide restricted relief and may result in undesirable side effects, posing a substantial clinical challenge. Peripheral and spinal redox homeostasis plays an important role in pain processing and perception. However, the roles of oxidative stress and antioxidants in pain and analgesia on the cortical region during chronic pain remains obscure. Here we focus on the ventrolateral orbital cortex (VLO), a brain region associated with pain severity and involved in pain inhibition. Using a spared nerve injury mouse model, we observed the notable reactive oxygen species (ROS)-mediated suppression of the excitability of pyramidal cells (PYRVLO) in the VLO. Nasal application or microinjection of the natural antioxidants proanthocyanidins (PACs) to the VLO specifically increased the activity of PYRVLO and induced a significant analgesic effect. Mechanistically, PACs activate PYRVLO by inhibiting distinct potassium channels in different ways: (1) by scavenging ROS to reduce ROS-sensitive voltage-gated potassium currents and (2) by acting as a channel blocker through direct binding to the cap structure of KCNK3 to inhibit the leak potassium current (Ileak). These results reveal the role of cortical oxidative stress in central hyperalgesia and elucidate the mechanism and potential translational significance of PACs in central analgesia. These findings suggest that the effects of PACs extend beyond their commonly assumed antioxidant or anti-inflammatory effects. Neuropathic pain is a challenging condition that affects the nervous system, causing abnormal sensations and heightened sensitivity. Researchers explored the potential of proanthocyanidins, natural antioxidants found in plants, to alleviate neuropathic pain. The study involves experiments on mice with nerve injuries to mimic neuropathic pain. Researchers administered proanthocyanidins to the ventrolateral orbitofrontal cortex, a key brain region for pain regulation. They measured pain responses and examined brain activity using various techniques, including electrode recordings and molecular analysis. Results showed that proanthocyanidins decreased pain sensitivity in mice by lowering oxidative stress and modulating specific potassium channels that help control nerve cell activity. This dual mechanism—antioxidant effects and potassium channel regulation—highlights proanthocyanidins as an alternative to conventional pain treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 3","pages":"567-583"},"PeriodicalIF":9.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01412-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}