Pub Date : 2025-01-10DOI: 10.1016/j.cellsig.2025.111590
Jingyu Zhu , Zihao Jian , Fangteng Liu , Lulu Le
Small nucleolar RNA host gene 10 (SNHG10) is a newly recognized long non-coding RNA (lncRNA) with significant implications in cancer biology. Abnormal expression of SNHG10 has been observed in various solid tumors and hematological malignancies. Research conducted in vivo and in vitro has revealed that SNHG10 plays a pivotal role in numerous biological processes, including cell proliferation, apoptosis, invasion and migration, drug resistance, energy metabolism, immune evasion, as well as tumor growth and metastasis. SNHG10 regulates tumor development through several mechanisms, such as competing with microRNA (miRNA) for binding sites, modulating various signaling pathways, influencing transcriptional activity, and affecting epigenetic regulation. The diverse biological functions and intricate mechanisms of SNHG10 highlight its considerable clinical relevance, positioning it as a potential pan-cancer biomarker and therapeutic target. This review aims to summarize the role of SNHG10 in tumorigenesis and cancer progression, clarify the molecular mechanisms at play, and explore its clinical significance in cancer diagnosis and prognosis prediction, along with its therapeutic potential.
{"title":"The emerging landscape of small nucleolar RNA host gene 10 in cancer mechanistic insights and clinical relevance","authors":"Jingyu Zhu , Zihao Jian , Fangteng Liu , Lulu Le","doi":"10.1016/j.cellsig.2025.111590","DOIUrl":"10.1016/j.cellsig.2025.111590","url":null,"abstract":"<div><div>Small nucleolar RNA host gene 10 (SNHG10) is a newly recognized long non-coding RNA (lncRNA) with significant implications in cancer biology. Abnormal expression of SNHG10 has been observed in various solid tumors and hematological malignancies. Research conducted in vivo and in vitro has revealed that SNHG10 plays a pivotal role in numerous biological processes, including cell proliferation, apoptosis, invasion and migration, drug resistance, energy metabolism, immune evasion, as well as tumor growth and metastasis. SNHG10 regulates tumor development through several mechanisms, such as competing with microRNA (miRNA) for binding sites, modulating various signaling pathways, influencing transcriptional activity, and affecting epigenetic regulation. The diverse biological functions and intricate mechanisms of SNHG10 highlight its considerable clinical relevance, positioning it as a potential pan-cancer biomarker and therapeutic target. This review aims to summarize the role of SNHG10 in tumorigenesis and cancer progression, clarify the molecular mechanisms at play, and explore its clinical significance in cancer diagnosis and prognosis prediction, along with its therapeutic potential.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111590"},"PeriodicalIF":4.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969822","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}
Pub Date : 2025-01-10DOI: 10.1016/j.cellsig.2025.111594
Zhi-bo Liu , Rong-rong Zhu , Jin-long Liu , Qi-rong Xu , Hua Xu , Ji-chun Liu , Xue-liang Zhou
Pulmonary artery hypertension (PAH) is characterized by a cancer-like metabolic shift towards aerobic glycolysis. Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone methyltransferase, has been implicated in PAH, yet its precise role remains unclear. In this study, we induced PAH in C57BL/6 mice using monocrotaline (MCT) and observed increased FOLR1 expression in PAH tissues, which was suppressed by NSD2 knockdown. Silencing NSD2 or FOLR1 inhibited the proliferation and migration of pulmonary artery endothelial cells (PAECs) and alleviated PAH phenotypes, right ventricular dysfunction, and pulmonary artery remodeling. Mechanistically, NSD2 knockdown prevented nuclear translocation of FOLR1 and its interaction with H3K36me2. Metabolic analysis revealed that NSD2 or FOLR1 knockdown reversed the increased oxygen consumption rate, extracellular acidification rate, glucose consumption, lactate production, and G6PD activity in MCT-treated PAECs. Furthermore, NSD2 or FOLR1 silencing decreased the expression of key glycolytic genes (HK2, TIGAR, and G6PD) by suppressing their promoter activity and weakening the interaction between FOLR1/H3K36me2 and these gene promoters. Our findings suggest that NSD2-mediated H3K36me2 recruits FOLR1 to promote PAH, and FOLR1 acts as a transcriptional factor to upregulate glycolytic gene expression in PAECs.
{"title":"NSD2 mediated H3K36me2 promotes pulmonary arterial hypertension by recruiting FOLR1 and metabolism reprogramming","authors":"Zhi-bo Liu , Rong-rong Zhu , Jin-long Liu , Qi-rong Xu , Hua Xu , Ji-chun Liu , Xue-liang Zhou","doi":"10.1016/j.cellsig.2025.111594","DOIUrl":"10.1016/j.cellsig.2025.111594","url":null,"abstract":"<div><div>Pulmonary artery hypertension (PAH) is characterized by a cancer-like metabolic shift towards aerobic glycolysis. Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone methyltransferase, has been implicated in PAH, yet its precise role remains unclear. In this study, we induced PAH in C57BL/6 mice using monocrotaline (MCT) and observed increased FOLR1 expression in PAH tissues, which was suppressed by NSD2 knockdown. Silencing NSD2 or FOLR1 inhibited the proliferation and migration of pulmonary artery endothelial cells (PAECs) and alleviated PAH phenotypes, right ventricular dysfunction, and pulmonary artery remodeling. Mechanistically, NSD2 knockdown prevented nuclear translocation of FOLR1 and its interaction with H3K36me2. Metabolic analysis revealed that NSD2 or FOLR1 knockdown reversed the increased oxygen consumption rate, extracellular acidification rate, glucose consumption, lactate production, and G6PD activity in MCT-treated PAECs. Furthermore, NSD2 or FOLR1 silencing decreased the expression of key glycolytic genes (HK2, TIGAR, and G6PD) by suppressing their promoter activity and weakening the interaction between FOLR1/H3K36me2 and these gene promoters. Our findings suggest that NSD2-mediated H3K36me2 recruits FOLR1 to promote PAH, and FOLR1 acts as a transcriptional factor to upregulate glycolytic gene expression in PAECs.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111594"},"PeriodicalIF":4.4,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969790","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}
Pub Date : 2025-01-09DOI: 10.1016/j.cellsig.2025.111591
Wenjing Liu , Yueli Ni , Wenjie Wang , Kun Cui , Qiuxin Duan , Ziyuan Bai , Asif Shahzad , Xiangjie Liu , Yurong Dong , Zhe Xu , Jinshan Zhang , Dongmei Peng , Zhuoran Teng , Yanping Gao , Zhe Yang , Qiao Zhang
Clear cell renal cell carcinoma (ccRCC), a predominant subtype of renal cell carcinoma, significantly contributes to the heightened morbidity and mortality in individuals diagnosed with urologic tumors. The challenges posed by high malignancy at the initial diagnosis of ccRCC, therapeutic resistance, and unfavorable patient prognosis remain largely unresolved. Our findings indicate that SEPT5 is upregulated in ccRCC and this upregulation is associated with an adverse prognosis for ccRCC patients. Furthermore, we demonstrate that overexpression of SEPT5 promotes proliferation of ccRCC cells, alters their cell cycle distribution, and enhances their migratory and invasive capabilities. Additionally, we observe a positive correlation between SEPT5 overexpression and resistance to sorafenib and sunitinib in ccRCC cells. Further mechanistic investigations have revealed that SEPT5 serves as a novel direct transcriptional target of HIF-1α, leading to subsequent reduction in protein expression and nuclear translocation of HIF-1α. This establishes a feedback loop in ccRCC tumorigenesis. Ultimately, knockdown of SEPT5 significantly inhibits xenografted tumor growth in vivo. Overall, this study provides compelling evidence that directly targeting the HIF-1α-SEPT5 feedback axis may be an effective approach for suppressing the proliferation and progression of ccRCC, offering new insights into the diagnosis and treatment of ccRCC patients.
{"title":"SEPT5 overexpression predicts poor prognosis and promotes progression through feedback regulation of HIF-1α in clear cell renal cell carcinoma","authors":"Wenjing Liu , Yueli Ni , Wenjie Wang , Kun Cui , Qiuxin Duan , Ziyuan Bai , Asif Shahzad , Xiangjie Liu , Yurong Dong , Zhe Xu , Jinshan Zhang , Dongmei Peng , Zhuoran Teng , Yanping Gao , Zhe Yang , Qiao Zhang","doi":"10.1016/j.cellsig.2025.111591","DOIUrl":"10.1016/j.cellsig.2025.111591","url":null,"abstract":"<div><div>Clear cell renal cell carcinoma (ccRCC), a predominant subtype of renal cell carcinoma, significantly contributes to the heightened morbidity and mortality in individuals diagnosed with urologic tumors. The challenges posed by high malignancy at the initial diagnosis of ccRCC, therapeutic resistance, and unfavorable patient prognosis remain largely unresolved. Our findings indicate that SEPT5 is upregulated in ccRCC and this upregulation is associated with an adverse prognosis for ccRCC patients. Furthermore, we demonstrate that overexpression of SEPT5 promotes proliferation of ccRCC cells, alters their cell cycle distribution, and enhances their migratory and invasive capabilities. Additionally, we observe a positive correlation between SEPT5 overexpression and resistance to sorafenib and sunitinib in ccRCC cells. Further mechanistic investigations have revealed that SEPT5 serves as a novel direct transcriptional target of HIF-1α, leading to subsequent reduction in protein expression and nuclear translocation of HIF-1α. This establishes a feedback loop in ccRCC tumorigenesis. Ultimately, knockdown of SEPT5 significantly inhibits xenografted tumor growth in vivo. Overall, this study provides compelling evidence that directly targeting the HIF-1α-SEPT5 feedback axis may be an effective approach for suppressing the proliferation and progression of ccRCC, offering new insights into the diagnosis and treatment of ccRCC patients.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111591"},"PeriodicalIF":4.4,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969786","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}
Pub Date : 2025-01-09DOI: 10.1016/j.cellsig.2025.111601
Qingyuan Gao , Meijing Wang , Xiangyi Hou , Meiying Li , Lisha Li
Most osteosarcoma (OS) cases exhibit poor differentiation at the histopathological level. Disruption of the normal osteogenic differentiation process results in the unregulated proliferation of precursor cells, which is a critical factor in the development of OS. Differentiation therapy aims to slow disease progression by restoring the osteogenic differentiation process of OS cells and is considered a new approach to treating OS. However, there are currently few studies on the mechanism of differentiation of OS, which puts the development of differentiation therapeutic drugs into a bottleneck. Substrate stiffness can regulate differentiation in mesenchymal stem cells. Evidence supports that mesenchymal stem cells and osteoblast precursors are the origin of OS. In this study, we simulated different stiffnesses in vitro to investigate the mechanism of substrate stiffness affecting differentiation of OS. We demonstrate that Piezo type mechanosensitive ion channel component 1 (PIEZO1) plays a critical regulatory role in sensing substrate stiffness in osteogenic and adipogenic differentiation of OS. When OS cells are cultured on the stiff substrate, integrin subunit beta 1 (ITGB1) increases and cooperates with PIEZO1 to promote Yes-Associated Protein (YAP) entering the nucleus, and may inhibit EZH2, thereby inhibiting H3K27me3 and increasing RUNX2 expression, and cells differentiate toward osteogenesis. Our results provide new insights for research on differentiation treatment of OS and are expected to help identify new targets for future drug design.
大多数骨肉瘤（OS）病例在组织病理学层面上表现为分化不良。正常成骨分化过程的破坏会导致前体细胞的无序增殖，这是骨肉瘤发病的关键因素。分化疗法旨在通过恢复OS细胞的成骨分化过程来延缓疾病进展，被认为是治疗OS的一种新方法。然而，目前关于OS分化机制的研究很少，这使得分化治疗药物的研发陷入瓶颈。基底硬度可调节间充质干细胞的分化。有证据表明，间充质干细胞和成骨细胞前体是OS的起源。在这项研究中，我们在体外模拟了不同的硬度，以研究基底硬度影响 OS 分化的机制。我们证明了压电型机械敏感离子通道成分1（PIEZO1）在OS成骨和成脂分化过程中感知基质硬度的关键调控作用。当OS细胞在坚硬的基质上培养时，整合素亚基β1（ITGB1）会增加，并与PIEZO1合作促进Yes-Associated蛋白（YAP）进入细胞核。YAP 进入细胞核后可能会抑制 EZH2，从而抑制 H3K27me3 并增加 RUNX2 的表达，细胞也会向成骨方向分化。我们的研究结果为OS的分化治疗研究提供了新的见解，并有望帮助确定未来药物设计的新靶点。
{"title":"Substrate stiffness modulates osteogenic and adipogenic differentiation of osteosarcoma through PIEZO1 mediated signaling pathway","authors":"Qingyuan Gao , Meijing Wang , Xiangyi Hou , Meiying Li , Lisha Li","doi":"10.1016/j.cellsig.2025.111601","DOIUrl":"10.1016/j.cellsig.2025.111601","url":null,"abstract":"<div><div>Most osteosarcoma (OS) cases exhibit poor differentiation at the histopathological level. Disruption of the normal osteogenic differentiation process results in the unregulated proliferation of precursor cells, which is a critical factor in the development of OS. Differentiation therapy aims to slow disease progression by restoring the osteogenic differentiation process of OS cells and is considered a new approach to treating OS. However, there are currently few studies on the mechanism of differentiation of OS, which puts the development of differentiation therapeutic drugs into a bottleneck. Substrate stiffness can regulate differentiation in mesenchymal stem cells. Evidence supports that mesenchymal stem cells and osteoblast precursors are the origin of OS. In this study, we simulated different stiffnesses in vitro to investigate the mechanism of substrate stiffness affecting differentiation of OS. We demonstrate that Piezo type mechanosensitive ion channel component 1 (PIEZO1) plays a critical regulatory role in sensing substrate stiffness in osteogenic and adipogenic differentiation of OS. When OS cells are cultured on the stiff substrate, integrin subunit beta 1 (ITGB1) increases and cooperates with PIEZO1 to promote Yes-Associated Protein (YAP) entering the nucleus, and may inhibit EZH2, thereby inhibiting H3K27me3 and increasing RUNX2 expression, and cells differentiate toward osteogenesis. Our results provide new insights for research on differentiation treatment of OS and are expected to help identify new targets for future drug design.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111601"},"PeriodicalIF":4.4,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969819","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}
Pub Date : 2025-01-08DOI: 10.1016/j.cellsig.2025.111600
Fei Ma , Xiji Qin , Junjie Yang , Xin Zhou , Jianyuan Zhao , Ke Cai , Rui Zhao , Yan Shi , Kun Sun
Fructose, as a natural and simple sugar, is not significantly harmful to the human body when consumed in moderation and can provide energy for the body. High-fructose diets have been linked to an increased risk of a range of metabolic disorders, including hypertriglyceridemia, hypertension, and diabetes mellitus. These conditions are known to be associated with an elevated risk of developing cardiometabolic diseases. Cardiomyocytes in mammals possess the capacity to proliferate from the moment of their birth. However, this capacity diminishes over time, and cardiac growth is ultimately achieved through cardiomyocyte (CM) hypertrophy. Prior studies have demonstrated that fructose metabolism is enhanced in the heart during pathological hypertrophy [1]. The consumption of foods containing high levels of fructose has been linked to an increase in the size of cardiomyocytes, which can lead to damage to the heart. The impact of high fructose on cardiomyocytes at the point of their initial capacity for proliferation has not been previously documented. In this experiment, our purpose was to explore the impact of high fructose in cardiomyocyte proliferation. To establish an apical resection model in neonatal mice, neonatal ICR mice were randomly divided into a sham-operated group (Sham + PBS), a sham-operated combined high-fructose group (Sham + fructose), an apical resection alone group (AR + PBS) and an apical resection combined with a high-fructose group (AR + fructose). Next, echocardiography was employed to assess the cardiac function of all mice. Masson staining was carried out to analyze cardiac fibrosis. Immunostaining was performed by extracting primary rat cardiomyocytes after the high-fructose intervention to see if proliferation-related markers (Ki67, PH3, Aurora-B) changed, qRT-PCR and immunofluorescence were used to determine changes in the expression profile of Notch1 in the neonatal heart. The results suggest that high fructose could inhibit cardiomyocyte proliferation in vivo and in vitro, The possible mechanism is that high fructose levels inhibit cardiomyocyte proliferation through suppression of Notch1 signaling pathway. In conclusion, high fructose levels inhibit the proliferation of cardiomyocytes via the Notch1 signaling pathway.
{"title":"High fructose levels inhibit the proliferation of cardiomyocytes via the Notch1 signaling pathway","authors":"Fei Ma , Xiji Qin , Junjie Yang , Xin Zhou , Jianyuan Zhao , Ke Cai , Rui Zhao , Yan Shi , Kun Sun","doi":"10.1016/j.cellsig.2025.111600","DOIUrl":"10.1016/j.cellsig.2025.111600","url":null,"abstract":"<div><div>Fructose, as a natural and simple sugar, is not significantly harmful to the human body when consumed in moderation and can provide energy for the body. High-fructose diets have been linked to an increased risk of a range of metabolic disorders, including hypertriglyceridemia, hypertension, and diabetes mellitus. These conditions are known to be associated with an elevated risk of developing cardiometabolic diseases. Cardiomyocytes in mammals possess the capacity to proliferate from the moment of their birth. However, this capacity diminishes over time, and cardiac growth is ultimately achieved through cardiomyocyte (CM) hypertrophy. Prior studies have demonstrated that fructose metabolism is enhanced in the heart during pathological hypertrophy [1]. The consumption of foods containing high levels of fructose has been linked to an increase in the size of cardiomyocytes, which can lead to damage to the heart. The impact of high fructose on cardiomyocytes at the point of their initial capacity for proliferation has not been previously documented. In this experiment, our purpose was to explore the impact of high fructose in cardiomyocyte proliferation. To establish an apical resection model in neonatal mice, neonatal ICR mice were randomly divided into a sham-operated group (Sham + PBS), a sham-operated combined high-fructose group (Sham + fructose), an apical resection alone group (AR + PBS) and an apical resection combined with a high-fructose group (AR + fructose). Next, echocardiography was employed to assess the cardiac function of all mice. Masson staining was carried out to analyze cardiac fibrosis. Immunostaining was performed by extracting primary rat cardiomyocytes after the high-fructose intervention to see if proliferation-related markers (Ki67, PH3, Aurora-B) changed, qRT-PCR and immunofluorescence were used to determine changes in the expression profile of Notch1 in the neonatal heart. The results suggest that high fructose could inhibit cardiomyocyte proliferation in vivo and in vitro, The possible mechanism is that high fructose levels inhibit cardiomyocyte proliferation through suppression of Notch1 signaling pathway. In conclusion, high fructose levels inhibit the proliferation of cardiomyocytes via the Notch1 signaling pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111600"},"PeriodicalIF":4.4,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964138","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}
Pub Date : 2025-01-07DOI: 10.1016/j.cellsig.2025.111598
Dong Wang , Jiahui Shen , Yan Wang , Hongwei Cui , Yanxin Li , Liyun Zhou , Guang Li , Qiyu Wang , Xiaotian Feng , Mengran Qin , Benchao Dong , Peichuan Yang , Yan Li , Xinlong Ma , Jianxiong Ma
Osteoporosis (OP) is a common disease in the elderly, characterized by decreased bone strength, reduced bone density, and increased fracture risk. There are two clinical types of osteoporosis: primary osteoporosis and secondary osteoporosis. The most common form is postmenopausal osteoporosis, which is caused by decreased estrogen production after menopause. Secondary osteoporosis, on the other hand, occurs when certain medications, diabetes, or nutritional deficiencies lead to a decrease in bone density. Ferroptosis, a new iron-dependent programmed cell death process, is critical in regulating the development of osteoporosis, but the underlying molecular mechanisms are complex. In the pathologic process of osteoporosis, several studies have found that ferroptosis may occur in osteocytes, osteoblasts, and osteoclasts, cell types closely related to bone metabolism. The imbalance of iron homeostasis in osteoblasts and excessive iron accumulation can promote lipid peroxidation through the Fenton reaction, which induces ferroptosis in osteoblasts and affects their role in regulating bone metabolism. Ferroptosis in osteoblasts inhibits bone formation and reduces the amount of new bone production. Osteoclast-associated ferroptosis abnormalities, on the other hand, may alter the homeostasis of bone resorption. In this paper, we start from the molecular mechanism of ferroptosis, and introduce the ways in which ferroptosis affects the physiological and pathological processes of the body. After that, the effects of ferroptosis on osteoblasts and osteoclasts will be discussed separately to elucidate the molecular mechanism between ferroptosis and osteoporosis, which will provide a new breakthrough for the prevention and treatment of osteoporosis and a more effective and better idea for the treatment strategy of osteoporosis.
{"title":"Mechanisms of Ferroptosis in bone disease: A new target for osteoporosis treatment","authors":"Dong Wang , Jiahui Shen , Yan Wang , Hongwei Cui , Yanxin Li , Liyun Zhou , Guang Li , Qiyu Wang , Xiaotian Feng , Mengran Qin , Benchao Dong , Peichuan Yang , Yan Li , Xinlong Ma , Jianxiong Ma","doi":"10.1016/j.cellsig.2025.111598","DOIUrl":"10.1016/j.cellsig.2025.111598","url":null,"abstract":"<div><div>Osteoporosis (OP) is a common disease in the elderly, characterized by decreased bone strength, reduced bone density, and increased fracture risk. There are two clinical types of osteoporosis: primary osteoporosis and secondary osteoporosis. The most common form is postmenopausal osteoporosis, which is caused by decreased estrogen production after menopause. Secondary osteoporosis, on the other hand, occurs when certain medications, diabetes, or nutritional deficiencies lead to a decrease in bone density. Ferroptosis, a new iron-dependent programmed cell death process, is critical in regulating the development of osteoporosis, but the underlying molecular mechanisms are complex. In the pathologic process of osteoporosis, several studies have found that ferroptosis may occur in osteocytes, osteoblasts, and osteoclasts, cell types closely related to bone metabolism. The imbalance of iron homeostasis in osteoblasts and excessive iron accumulation can promote lipid peroxidation through the Fenton reaction, which induces ferroptosis in osteoblasts and affects their role in regulating bone metabolism. Ferroptosis in osteoblasts inhibits bone formation and reduces the amount of new bone production. Osteoclast-associated ferroptosis abnormalities, on the other hand, may alter the homeostasis of bone resorption. In this paper, we start from the molecular mechanism of ferroptosis, and introduce the ways in which ferroptosis affects the physiological and pathological processes of the body. After that, the effects of ferroptosis on osteoblasts and osteoclasts will be discussed separately to elucidate the molecular mechanism between ferroptosis and osteoporosis, which will provide a new breakthrough for the prevention and treatment of osteoporosis and a more effective and better idea for the treatment strategy of osteoporosis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111598"},"PeriodicalIF":4.4,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945228","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}
Pub Date : 2025-01-06DOI: 10.1016/j.cellsig.2025.111593
Jiaojiao Xia , Wenjing Liu , Yueli Ni , Asif Shahzad , Kun Cui , Zhe Xu , Jinshan Zhang , Zhenyan Wei , Zhuoran Teng , Zhe Yang , Qiao Zhang
ASS1(argininosuccinate synthase 1) is a rate-limiting enzyme in the urea cycle, catalyzing the synthesis of argininosuccinate from citrulline and aspartate to ultimately produce arginine and support cellular metabolism. Increasing evidence suggests that ASS1 is commonly dysregulated in the tumor microenvironment, promoting tumor cell metastasis and infiltration. With a deeper understanding of tumor metabolic reprogramming in recent years, the impact of ASS1 dysregulation on abnormal tumor metabolism has attracted growing interest among researchers. In tumors with lacked or downregulated expression of ASS1, tumor cells become ‘addicted’ to exogenous arginine. Several strategies for arginine deprivation have been developed and entered clinical trials for treating such tumors. Therefore, we focus on elucidating the commonalities and characteristics of ASS1 dysregulation in tumors, as well as its implications for diagnosis, treatment, and prognosis. The mechanisms by which ASS1 gene dysregulation leads to metabolic abnormalities in tumor cells vary across different types of tumors. Extensive experimental studies have demonstrated that overexpression or low expression of ASS1 exhibits varying effects—either inhibitory or stimulatory proliferation—on tumor cells across different types. Restoring its expression can inhibit proliferation in some tumors lacking or downregulating ASS1 but can promote metastasis and infiltration in others (e.g., resistance to arginine deprivation therapy). Additionally, the expression level of ASS1 dynamically changes during tumorigenesis and progression. Finally, this review discusses the diagnostic, therapeutic, and prognostic value of ASS1 in future clinical practice.
{"title":"Advances in the impact of ASS1 dysregulation on metabolic reprogramming of tumor cells","authors":"Jiaojiao Xia , Wenjing Liu , Yueli Ni , Asif Shahzad , Kun Cui , Zhe Xu , Jinshan Zhang , Zhenyan Wei , Zhuoran Teng , Zhe Yang , Qiao Zhang","doi":"10.1016/j.cellsig.2025.111593","DOIUrl":"10.1016/j.cellsig.2025.111593","url":null,"abstract":"<div><div>ASS1(argininosuccinate synthase 1) is a rate-limiting enzyme in the urea cycle, catalyzing the synthesis of argininosuccinate from citrulline and aspartate to ultimately produce arginine and support cellular metabolism. Increasing evidence suggests that ASS1 is commonly dysregulated in the tumor microenvironment, promoting tumor cell metastasis and infiltration. With a deeper understanding of tumor metabolic reprogramming in recent years, the impact of ASS1 dysregulation on abnormal tumor metabolism has attracted growing interest among researchers. In tumors with lacked or downregulated expression of ASS1, tumor cells become ‘addicted’ to exogenous arginine. Several strategies for arginine deprivation have been developed and entered clinical trials for treating such tumors. Therefore, we focus on elucidating the commonalities and characteristics of ASS1 dysregulation in tumors, as well as its implications for diagnosis, treatment, and prognosis. The mechanisms by which ASS1 gene dysregulation leads to metabolic abnormalities in tumor cells vary across different types of tumors. Extensive experimental studies have demonstrated that overexpression or low expression of ASS1 exhibits varying effects—either inhibitory or stimulatory proliferation—on tumor cells across different types. Restoring its expression can inhibit proliferation in some tumors lacking or downregulating ASS1 but can promote metastasis and infiltration in others (e.g., resistance to arginine deprivation therapy). Additionally, the expression level of ASS1 dynamically changes during tumorigenesis and progression. Finally, this review discusses the diagnostic, therapeutic, and prognostic value of ASS1 in future clinical practice.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111593"},"PeriodicalIF":4.4,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944906","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}
Pub Date : 2025-01-05DOI: 10.1016/j.cellsig.2025.111592
Jie Liu , Mei-qi He , Gao-peng Guan, Xin-xing Wan , Ping Jin
Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia caused by the destruction of insulin-producing β cells. Viral infection is an important environmental factor which is associated with the islet autoimmunity in genetically susceptible individuals. Loss of β-cells and triggering of insulitis following viral infection could result from several non-exclusive mechanisms. Despite a significant increase in ISG15 levels following viral infection, the specific role of ISG15 in the impairment of insulin-producing β-cells is unclear. To address this issue at the clinical level, we conducted this experimental work, and found elevated levels of ISG15 in the peripheral blood of T1D patients, suggesting a potential link between ISG15 and T1D. In the T1D animal model, we discovered that both ISG15 levels and cellular apoptosis were increased in pancreatic islet tissue. To investigate at the cellular level, we cultured MIN6 cells in the presence of supernatants derived from iBMDM cells transfected with poly(I:C) (PIC), a viral mimic. This exposure led to an upregulation of ISG15 expression in MIN6 cells, which was accompanied by the suppression of their functional capabilities and viability. Intriguingly, the direct transfection of MIN6 cells with PIC increased the expression of ISG15. We further found that elevated levels of ISG15 had a direct inhibitory effect on insulin secretion and it also contributed to β-cell apoptosis in a TNF-α-dependent manner. In conclusion, our study revealed a potential underlying mechanism through which ISG15 increases the apoptosis of β-cells, providing valuable insights that could facilitate the development of T1D treatment strategies.
{"title":"ISG15 increases the apoptosis of β cells in type 1 diabetes","authors":"Jie Liu , Mei-qi He , Gao-peng Guan, Xin-xing Wan , Ping Jin","doi":"10.1016/j.cellsig.2025.111592","DOIUrl":"10.1016/j.cellsig.2025.111592","url":null,"abstract":"<div><div>Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia caused by the destruction of insulin-producing β cells. Viral infection is an important environmental factor which is associated with the islet autoimmunity in genetically susceptible individuals. Loss of β-cells and triggering of insulitis following viral infection could result from several non-exclusive mechanisms. Despite a significant increase in ISG15 levels following viral infection, the specific role of ISG15 in the impairment of insulin-producing β-cells is unclear. To address this issue at the clinical level, we conducted this experimental work, and found elevated levels of ISG15 in the peripheral blood of T1D patients, suggesting a potential link between ISG15 and T1D. In the T1D animal model, we discovered that both ISG15 levels and cellular apoptosis were increased in pancreatic islet tissue. To investigate at the cellular level, we cultured MIN6 cells in the presence of supernatants derived from iBMDM cells transfected with poly(I:C) (PIC), a viral mimic. This exposure led to an upregulation of ISG15 expression in MIN6 cells, which was accompanied by the suppression of their functional capabilities and viability. Intriguingly, the direct transfection of MIN6 cells with PIC increased the expression of ISG15. We further found that elevated levels of ISG15 had a direct inhibitory effect on insulin secretion and it also contributed to β-cell apoptosis in a TNF-α-dependent manner. In conclusion, our study revealed a potential underlying mechanism through which ISG15 increases the apoptosis of β-cells, providing valuable insights that could facilitate the development of T1D treatment strategies.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111592"},"PeriodicalIF":4.4,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962055","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}
Pub Date : 2025-01-05DOI: 10.1016/j.cellsig.2025.111589
Chunhui Qi , Bin Cao , Zhiwen Gong , Weiyu Zhang , Pengfei Yang , Haorui Qin , Yan Zhao , Yingchun Chen
Metabolic reprogramming plays a critical role in tumorigenesis and progression, including hepatocellular carcinoma (HCC). The Solute Carriers (SLCs) family is responsible for the transport of a range of nutrients and has been linked to various cancers. Cancer stem cells (CSC) are a contributing factor to the recurrence and metastasis of HCC. However, the regulatory genes that govern this process remain unclear. The present study identified SLC35C2 as a crucial factor in maintaining the stem-cell characteristics of HCC cells through CRISPR-dCas9 screening. Further investigation demonstrated that SLC35C2 was significantly elevated in HCC tissues and correlated with a poor prognosis in HCC patients. It is an independent prognostic factor for HCC patients. The knockdown and overexpression of SLC35C2 inhibited or promoted stemness in HCC cell. Both in vitro and in vivo studies demonstrated that SLC35C2 promoted the proliferation, migration, invasion and metastasis in HCC cells. Through RNA-seq and lipidomics analysis, it was found that SLC35C2 regulated lipid reprogramming, particularly triglyceride synthesis. Mechanistically, SLC35C2 stimulated lipogenesis through the up-regulation of SREBP1, ACC, FAS, and SCD-1, thereby increasing lipid accumulation in HCC cells. SLC35C2 interacted with ACSL4, which plays a critical role in lipogenesis, and to protect it from degradation. Inhibition of ACSL4 with PRGL493 can reverse the lipogenesis, stemness and proliferation induced by SLC35C2 overexpression. In conclusion, our study demonstrates the pivotal role of SLC35C2 in stemness and malignant progression in HCC by promoting lipogenesis. These findings suggest that SLC35C2 is a prognostic marker and promising therapeutic target for HCC treatment.
{"title":"SLC35C2 promotes stemness and progression in hepatocellular carcinoma by activating lipogenesis","authors":"Chunhui Qi , Bin Cao , Zhiwen Gong , Weiyu Zhang , Pengfei Yang , Haorui Qin , Yan Zhao , Yingchun Chen","doi":"10.1016/j.cellsig.2025.111589","DOIUrl":"10.1016/j.cellsig.2025.111589","url":null,"abstract":"<div><div>Metabolic reprogramming plays a critical role in tumorigenesis and progression, including hepatocellular carcinoma (HCC). The Solute Carriers (SLCs) family is responsible for the transport of a range of nutrients and has been linked to various cancers. Cancer stem cells (CSC) are a contributing factor to the recurrence and metastasis of HCC. However, the regulatory genes that govern this process remain unclear. The present study identified SLC35C2 as a crucial factor in maintaining the stem-cell characteristics of HCC cells through CRISPR-dCas9 screening. Further investigation demonstrated that SLC35C2 was significantly elevated in HCC tissues and correlated with a poor prognosis in HCC patients. It is an independent prognostic factor for HCC patients. The knockdown and overexpression of SLC35C2 inhibited or promoted stemness in HCC cell. Both in vitro and in vivo studies demonstrated that SLC35C2 promoted the proliferation, migration, invasion and metastasis in HCC cells. Through RNA-seq and lipidomics analysis, it was found that SLC35C2 regulated lipid reprogramming, particularly triglyceride synthesis. Mechanistically, SLC35C2 stimulated lipogenesis through the up-regulation of SREBP1, ACC, FAS, and SCD-1, thereby increasing lipid accumulation in HCC cells. SLC35C2 interacted with ACSL4, which plays a critical role in lipogenesis, and to protect it from degradation. Inhibition of ACSL4 with PRGL493 can reverse the lipogenesis, stemness and proliferation induced by SLC35C2 overexpression. In conclusion, our study demonstrates the pivotal role of SLC35C2 in stemness and malignant progression in HCC by promoting lipogenesis. These findings suggest that SLC35C2 is a prognostic marker and promising therapeutic target for HCC treatment.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111589"},"PeriodicalIF":4.4,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142964137","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}
Pub Date : 2025-01-04DOI: 10.1016/j.cellsig.2025.111588
Etienne Billard , Alexandre Torbey , Antonio Inserra , Emily Grant , Antonella Bertazzo , Danilo De Gregorio , Stefano Comai , David Chatenet , Gabriella Gobbi , Terence E. Hébert
Promising clinical evidence suggests that psychedelic compounds, like lysergic acid diethylamide (LSD), have therapeutic value for treatment of psychiatric disorders. However, they often produce hallucinations and dissociative states, likely mediated by the serotonin (5-HT) receptor 5-HT2A, raising challenges regarding therapeutic scalability. Given the reported antipsychotic effects of cannabidiol (CBD) and its promiscuous binding at many receptors, we assessed whether CBD could modulate 5-HT2A signalling. Activation of the 5-HT2A intracellular signalling events were assessed using resonance energy transfer- or fluorescence-based biosensors in HEK 293 cells and in rat primary cortical neurons. In 5-HT2A-transfected HEK 293 T cells, CBD antagonized LSD-mediated Gq activation in a saturable way, while leaving β-arrestin2 recruitment unaffected. CBD decreased Gq activation mediated by the 5-HT2A-specific agonist DOI as well as LSD-mediated activity in primary rat neonatal cortical neurons. Using Site Identification by Ligand Competitive Saturation (SILCS) simulations, we also predicted that the putative binding site of CBD overlapped with that of oleamide, a positive allosteric modulator of 5-HT2A, and could displace the binding of orthosteric ligands toward the external binding pocket. Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT2A.
{"title":"Pharmacological characterization of cannabidiol as a negative allosteric modulator of the 5-HT2A receptor","authors":"Etienne Billard , Alexandre Torbey , Antonio Inserra , Emily Grant , Antonella Bertazzo , Danilo De Gregorio , Stefano Comai , David Chatenet , Gabriella Gobbi , Terence E. Hébert","doi":"10.1016/j.cellsig.2025.111588","DOIUrl":"10.1016/j.cellsig.2025.111588","url":null,"abstract":"<div><div>Promising clinical evidence suggests that psychedelic compounds, like lysergic acid diethylamide (LSD), have therapeutic value for treatment of psychiatric disorders. However, they often produce hallucinations and dissociative states, likely mediated by the serotonin (5-HT) receptor 5-HT<sub>2A</sub>, raising challenges regarding therapeutic scalability. Given the reported antipsychotic effects of cannabidiol (CBD) and its promiscuous binding at many receptors, we assessed whether CBD could modulate 5-HT<sub>2A</sub> signalling. Activation of the 5-HT<sub>2A</sub> intracellular signalling events were assessed using resonance energy transfer- or fluorescence-based biosensors in HEK 293 cells and in rat primary cortical neurons. In 5-HT<sub>2A</sub>-transfected HEK 293 T cells, CBD antagonized LSD-mediated Gq activation in a saturable way, while leaving β-arrestin2 recruitment unaffected. CBD decreased Gq activation mediated by the 5-HT<sub>2A</sub>-specific agonist DOI as well as LSD-mediated activity in primary rat neonatal cortical neurons. Using <em>S</em>ite <em>I</em>dentification by <em>L</em>igand <em>C</em>ompetitive <em>S</em>aturation (SILCS) simulations, we also predicted that the putative binding site of CBD overlapped with that of oleamide, a positive allosteric modulator of 5-HT<sub>2A</sub>, and could displace the binding of orthosteric ligands toward the external binding pocket. Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT<sub>2A</sub>.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111588"},"PeriodicalIF":4.4,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945679","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}
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