Pub Date : 2025-02-18DOI: 10.1038/s12276-025-01404-5
Si Chen, Yu-Bin Lee, Mi-Young Song, Changjin Lim, Hwangeui Cho, Hyun Joo Shim, Jong-Suk Kim, Byung-Hyun Park, Jeon-Kyung Kim, Eun Ju Bae
Cannabidiol (CBD), a nonpsychoactive compound from Cannabis, has various bioactive functions in humans and animals. Evidence suggests that CBD promotes muscle injury recovery in athletes, but whether and how CBD improves endurance performance remains unclear. Here we investigated the effects of CBD treatment on exercise performance in mice and assessed whether this effect involves the gut microbiome. CBD administration significantly increased treadmill running performance in mice, accompanied by an increase in oxidative myofiber composition. CBD also increased mitochondrial biogenesis and the expression of associated genes such as PGC-1α, phosphorylated CREB and AMPK in muscle tissue. Interestingly, CBD altered the composition of the gut microbiome, and antibiotic treatment reduced the muscle endurance-enhancing effects of CBD and mitochondrial biogenesis. We isolated Bifidobacterium animalis, a microbe increased by CBD administration, and named it KBP-1. Treatment with B. animalis KBP-1 in mice resulted in improved running performance. Whole-genome analysis revealed that B. animalis KBP-1 presented high expression of genes involved in branched-chain amino acid biosynthesis, expression of branched-chain amino acid release pumps and metabolism of lactic acid. In summary, our study identified CBD and B. animalis KBP-1 as potential endurance exercise-promoting agents. This study explores how cannabidiol (CBD), a compound from the Cannabis sativa plant, affects exercise performance and muscle function. The researchers wanted to see if CBD could improve endurance by changing gut bacteria. They found that CBD improved endurance and increased the presence of certain gut bacteria, including Bifidobacterium animalis, that may help muscles use energy more efficiently. The study involved treating mice with either CBD or B. animalis for 4 weeks and measuring their running ability on a treadmill. The researchers examined changes in muscle fibers and gut bacteria composition. They discovered that CBD and B. animalis increased oxidative muscle fibers, which benefit endurance performance. The results suggest that CBD enhances exercise performance by promoting beneficial gut bacteria and improving muscle energy use. The researchers conclude that both CBD and B. animalis could be used to boost endurance.
{"title":"Cannabidiol reshapes the gut microbiome to promote endurance exercise in mice","authors":"Si Chen, Yu-Bin Lee, Mi-Young Song, Changjin Lim, Hwangeui Cho, Hyun Joo Shim, Jong-Suk Kim, Byung-Hyun Park, Jeon-Kyung Kim, Eun Ju Bae","doi":"10.1038/s12276-025-01404-5","DOIUrl":"10.1038/s12276-025-01404-5","url":null,"abstract":"Cannabidiol (CBD), a nonpsychoactive compound from Cannabis, has various bioactive functions in humans and animals. Evidence suggests that CBD promotes muscle injury recovery in athletes, but whether and how CBD improves endurance performance remains unclear. Here we investigated the effects of CBD treatment on exercise performance in mice and assessed whether this effect involves the gut microbiome. CBD administration significantly increased treadmill running performance in mice, accompanied by an increase in oxidative myofiber composition. CBD also increased mitochondrial biogenesis and the expression of associated genes such as PGC-1α, phosphorylated CREB and AMPK in muscle tissue. Interestingly, CBD altered the composition of the gut microbiome, and antibiotic treatment reduced the muscle endurance-enhancing effects of CBD and mitochondrial biogenesis. We isolated Bifidobacterium animalis, a microbe increased by CBD administration, and named it KBP-1. Treatment with B. animalis KBP-1 in mice resulted in improved running performance. Whole-genome analysis revealed that B. animalis KBP-1 presented high expression of genes involved in branched-chain amino acid biosynthesis, expression of branched-chain amino acid release pumps and metabolism of lactic acid. In summary, our study identified CBD and B. animalis KBP-1 as potential endurance exercise-promoting agents. This study explores how cannabidiol (CBD), a compound from the Cannabis sativa plant, affects exercise performance and muscle function. The researchers wanted to see if CBD could improve endurance by changing gut bacteria. They found that CBD improved endurance and increased the presence of certain gut bacteria, including Bifidobacterium animalis, that may help muscles use energy more efficiently. The study involved treating mice with either CBD or B. animalis for 4 weeks and measuring their running ability on a treadmill. The researchers examined changes in muscle fibers and gut bacteria composition. They discovered that CBD and B. animalis increased oxidative muscle fibers, which benefit endurance performance. The results suggest that CBD enhances exercise performance by promoting beneficial gut bacteria and improving muscle energy use. The researchers conclude that both CBD and B. animalis could be used to boost endurance.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 2","pages":"489-500"},"PeriodicalIF":9.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01404-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450895","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}
Pub Date : 2025-02-13DOI: 10.1038/s12276-025-01403-6
Shi-Young Park, Yoonil Cho, Sae-Mi Son, Jang Ho Hur, Yeongmin Kim, Hyunhee Oh, Hui-Young Lee, Sungwon Jung, Sanghee Park, Il-Young Kim, Se-Jin Lee, Cheol Soo Choi
Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in NAFLD require further investigation. Here we found that hepatic Inhbe expression increased under prolonged fasting and ER stress conditions, which was mediated by ATF4, as determined by promoter analysis in a mouse model. Consistently, a positive correlation between INHBE and ATF4 expression levels in relation to NAFLD status was confirmed using public human NAFLD datasets. To investigate the role of activin E in hepatic steatosis, we assessed the fluxes of the lipid metabolism in an Inhbe-knockout mouse model. These mice displayed a lean phenotype but developed severe hepatic steatosis under a high-fat diet. The deficiency of Inhbe resulted in increased lipolysis in adipose tissue, leading to increased fatty acid influx into the liver. Conversely, hepatic overexpression of Inhbe ameliorated hepatic steatosis by suppressing lipolysis in adipose tissue through ALK7–Smad signaling. In conclusion, activin E serves as a regulatory hepatokine that prevents fatty acid influx into the liver, thereby protecting against NAFLD. Hepatic endoplasmic reticulum (ER) stress is associated with nonalcoholic fatty liver disease (NAFLD). Although it is known that the liver’s ER can activate defense mechanisms to slow NAFLD progression, the specific protective processes remain unclear. Recent studies have identified activin E, encoded by the Inhbe gene, as being linked to metabolic conditions such as insulin resistance and NAFLD. This research demonstrates that hepatic Inhbe expression increases during ER stress, a process regulated by ATF4. Loss of Inhbe led to severe hepatic steatosis due to enhanced lipolysis in adipose tissue. By contrast, hepatic overexpression of Inhbe alleviated hepatic steatosis by suppressing adipose tissue lipolysis through ALK7–Smad signaling. These findings suggest that activin E functions as a regulatory hepatokine, protecting against NAFLD by preventing excessive fatty acid influx into the liver through the inhibition of adipose lipolysis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue","authors":"Shi-Young Park, Yoonil Cho, Sae-Mi Son, Jang Ho Hur, Yeongmin Kim, Hyunhee Oh, Hui-Young Lee, Sungwon Jung, Sanghee Park, Il-Young Kim, Se-Jin Lee, Cheol Soo Choi","doi":"10.1038/s12276-025-01403-6","DOIUrl":"10.1038/s12276-025-01403-6","url":null,"abstract":"Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in NAFLD require further investigation. Here we found that hepatic Inhbe expression increased under prolonged fasting and ER stress conditions, which was mediated by ATF4, as determined by promoter analysis in a mouse model. Consistently, a positive correlation between INHBE and ATF4 expression levels in relation to NAFLD status was confirmed using public human NAFLD datasets. To investigate the role of activin E in hepatic steatosis, we assessed the fluxes of the lipid metabolism in an Inhbe-knockout mouse model. These mice displayed a lean phenotype but developed severe hepatic steatosis under a high-fat diet. The deficiency of Inhbe resulted in increased lipolysis in adipose tissue, leading to increased fatty acid influx into the liver. Conversely, hepatic overexpression of Inhbe ameliorated hepatic steatosis by suppressing lipolysis in adipose tissue through ALK7–Smad signaling. In conclusion, activin E serves as a regulatory hepatokine that prevents fatty acid influx into the liver, thereby protecting against NAFLD. Hepatic endoplasmic reticulum (ER) stress is associated with nonalcoholic fatty liver disease (NAFLD). Although it is known that the liver’s ER can activate defense mechanisms to slow NAFLD progression, the specific protective processes remain unclear. Recent studies have identified activin E, encoded by the Inhbe gene, as being linked to metabolic conditions such as insulin resistance and NAFLD. This research demonstrates that hepatic Inhbe expression increases during ER stress, a process regulated by ATF4. Loss of Inhbe led to severe hepatic steatosis due to enhanced lipolysis in adipose tissue. By contrast, hepatic overexpression of Inhbe alleviated hepatic steatosis by suppressing adipose tissue lipolysis through ALK7–Smad signaling. These findings suggest that activin E functions as a regulatory hepatokine, protecting against NAFLD by preventing excessive fatty acid influx into the liver through the inhibition of adipose lipolysis. 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 2","pages":"466-477"},"PeriodicalIF":9.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01403-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416141","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}
Pub Date : 2025-02-13DOI: 10.1038/s12276-025-01406-3
Ee Hyun Kim, Mi Kyung Kim, MiSun Choe, Ji Hyun Ryu, Eun Seon Pak, Hunjoo Ha, Eun-Jung Jin
Lipid metabolism, particularly fatty acid oxidation dysfunction, is a major driver of renal fibrosis. However, the detailed regulatory mechanisms underlying this process remain unclear. Here we demonstrated that acyl-CoA thioesterase 12 (Acot12), an enzyme involved in the hydrolysis of acyl-CoA thioesters into free fatty acids and CoA, is a key regulator of lipid metabolism in fibrotic kidneys. A significantly decreased level of ACOT12 was observed in kidney samples from human patients with chronic kidney disease as well as in samples from mice with kidney injuries. Acot12 deficiency induces lipid accumulation and fibrosis in mice subjected to unilateral ureteral obstruction (UUO). Fenofibrate administration does not reduce renal fibrosis in Acot12−/− mice with UUO. Moreover, the restoration of peroxisome proliferator-activated receptor α (PPARα) in Acot12−/−Pparα−/− kidneys with UUO exacerbated lipid accumulation and renal fibrosis, whereas the restoration of Acot12 in Acot12−/− Pparα−/− kidneys with UUO significantly reduced lipid accumulation and renal fibrosis, suggesting that, mechanistically, Acot12 deficiency exacerbates renal fibrosis independently of PPARα. In Acot12−/− kidneys with UUO, a reduction in the selective autophagic degradation of peroxisomes and pexophagy with a decreased level of ACBD5 was observed. In conclusion, our study demonstrates the functional role and mechanistic details of Acot12 in the progression of renal fibrosis, provides a preclinical rationale for regulating Acot12 expression and presents a novel means of preventing renal fibrosis. Chronic kidney disease (CKD) is a serious condition that affects kidney function over time. It can lead to other health problems, but current treatments are limited. Here the authors wanted to explore new ways to treat CKD by focusing on kidney fibrosis, a major factor in CKD progression. This study demonstrates that decreased level of ACOT12, a critical enzyme in lipid metabolism, correlates with increased fibrosis and lipid accumulation in the kidney tissues. Mice lacking ACOT12 had more kidney fibrosis and lipid accumulation, suggesting that ACOT12 plays a protective role, while restoring ACOT12 in these mice reduced fibrosis and lipid buildup. These findings suggest that targeting ACOT12 could be a novel therapeutic approach for preventing kidney fibrosis by regulating lipid metabolism in CKD. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"ACOT12, a novel factor in the pathogenesis of kidney fibrosis, modulates ACBD5","authors":"Ee Hyun Kim, Mi Kyung Kim, MiSun Choe, Ji Hyun Ryu, Eun Seon Pak, Hunjoo Ha, Eun-Jung Jin","doi":"10.1038/s12276-025-01406-3","DOIUrl":"10.1038/s12276-025-01406-3","url":null,"abstract":"Lipid metabolism, particularly fatty acid oxidation dysfunction, is a major driver of renal fibrosis. However, the detailed regulatory mechanisms underlying this process remain unclear. Here we demonstrated that acyl-CoA thioesterase 12 (Acot12), an enzyme involved in the hydrolysis of acyl-CoA thioesters into free fatty acids and CoA, is a key regulator of lipid metabolism in fibrotic kidneys. A significantly decreased level of ACOT12 was observed in kidney samples from human patients with chronic kidney disease as well as in samples from mice with kidney injuries. Acot12 deficiency induces lipid accumulation and fibrosis in mice subjected to unilateral ureteral obstruction (UUO). Fenofibrate administration does not reduce renal fibrosis in Acot12−/− mice with UUO. Moreover, the restoration of peroxisome proliferator-activated receptor α (PPARα) in Acot12−/−Pparα−/− kidneys with UUO exacerbated lipid accumulation and renal fibrosis, whereas the restoration of Acot12 in Acot12−/− Pparα−/− kidneys with UUO significantly reduced lipid accumulation and renal fibrosis, suggesting that, mechanistically, Acot12 deficiency exacerbates renal fibrosis independently of PPARα. In Acot12−/− kidneys with UUO, a reduction in the selective autophagic degradation of peroxisomes and pexophagy with a decreased level of ACBD5 was observed. In conclusion, our study demonstrates the functional role and mechanistic details of Acot12 in the progression of renal fibrosis, provides a preclinical rationale for regulating Acot12 expression and presents a novel means of preventing renal fibrosis. Chronic kidney disease (CKD) is a serious condition that affects kidney function over time. It can lead to other health problems, but current treatments are limited. Here the authors wanted to explore new ways to treat CKD by focusing on kidney fibrosis, a major factor in CKD progression. This study demonstrates that decreased level of ACOT12, a critical enzyme in lipid metabolism, correlates with increased fibrosis and lipid accumulation in the kidney tissues. Mice lacking ACOT12 had more kidney fibrosis and lipid accumulation, suggesting that ACOT12 plays a protective role, while restoring ACOT12 in these mice reduced fibrosis and lipid buildup. These findings suggest that targeting ACOT12 could be a novel therapeutic approach for preventing kidney fibrosis by regulating lipid metabolism in CKD. 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 2","pages":"478-488"},"PeriodicalIF":9.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01406-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143410770","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}
Pub Date : 2025-02-12DOI: 10.1038/s12276-025-01408-1
Jeong-Su Park, Jin Lee, Feng Wang, Hwan Ma, Zixiong Zhou, Yong-Sun Lee, Kwangyeon Oh, Haram Lee, Guoyan Sui, Sangkyu Lee, Yoon Mee Yang, Jang-Won Lee, Yong-Ha Ji, Chun-Woong Park, Hwan-Soo Yoo, Bang-Yeon Hwang, Sang-Bae Han, Nan Song, Soohwan Oh, Bumseok Kim, Ekihiro Seki, Jin Tae Hong, Yoon Seok Roh
Metabolic dysfunction-associated steatohepatitis (MASH) is associated with the activation of Kupffer cells (KCs) and hepatic stellate cells, at which point a metabolically stressed hepatocyte becomes integral to the progression of the disease. We observed a significant reduction in the level of alpha-1-antitrypsin (A1AT), a hepatocyte-derived secreted factor, in both patients with MASH and mice fed a fast-food diet (FFD). KC-mediated hepatic inflammation, most notably IL-1β, led to the transcriptional inhibition of A1AT by HNF4α. In quintuple Serpina1a–e knockout mice, ablation of A1AT worsened MASH through increased activity of proteinase 3 (PR3), a proinflammatory protease produced by F4/80hi/CD11blow/TIM4−/CCR2+ monocyte-derived KCs (MoKCs). Conversely, A1AT restoration or PR3 inhibition mitigated MASH progression. A PR3-bound cytokine array identified IL-32 as a key factor associated with MASH. Combining IL-32 with SERPINA1, the gene encoding A1AT, synergistically predicted patients at risk of MASH through univariate logistic regression analysis. Furthermore, in vivo overexpression of IL-32γ alleviated MASH induced by FFD. However, additional knockout of A1AT increased PR3 activity, consequently abolishing the anti-MASH effects of IL-32γ. Blocking PR3-mediated IL-32γ cleavage via the V104A mutation sustained its protective actions, while the PR3-cleaved C-terminal fragment activated KCs. Additionally, after cleavage, the antifibrogenic effect of IL-32γ is lost, resulting in a failure to prevent the activation of hepatic stellate cells. This study highlights the critical role of hepatocyte-derived A1AT in the PR3/IL-32γ axis during MASH development. Strategies to correct A1AT dysregulation, such as A1AT supplementation or PR3 inhibition with sivelestat, may offer protection against the development and progression of MASH and fibrosis. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver failure worldwide. Researchers are trying to understand how it progresses to more severe conditions such as metabolic dysfunction-associated steatohepatitis (MASH). This study focuses on a protein called alpha-1-antitrypsin, which is important for liver health. The researchers used mice and human samples to study the role of A1AT in liver disease. They found that A1AT levels are lower in people and mice with MASLD, which leads to increased inflammation and liver damage. They also discovered that a protein called proteinase 3 becomes more active when A1AT is low, worsening the condition. By experimenting with mice, they showed that increasing A1AT or blocking PR3 can reduce liver damage. This suggests new treatment possibilities for MASH. The study concludes that targeting the A1AT/PR3 pathway could help manage liver disease progression. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"A1AT dysregulation of metabolically stressed hepatocytes by Kupffer cells drives MASH and fibrosis","authors":"Jeong-Su Park, Jin Lee, Feng Wang, Hwan Ma, Zixiong Zhou, Yong-Sun Lee, Kwangyeon Oh, Haram Lee, Guoyan Sui, Sangkyu Lee, Yoon Mee Yang, Jang-Won Lee, Yong-Ha Ji, Chun-Woong Park, Hwan-Soo Yoo, Bang-Yeon Hwang, Sang-Bae Han, Nan Song, Soohwan Oh, Bumseok Kim, Ekihiro Seki, Jin Tae Hong, Yoon Seok Roh","doi":"10.1038/s12276-025-01408-1","DOIUrl":"10.1038/s12276-025-01408-1","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH) is associated with the activation of Kupffer cells (KCs) and hepatic stellate cells, at which point a metabolically stressed hepatocyte becomes integral to the progression of the disease. We observed a significant reduction in the level of alpha-1-antitrypsin (A1AT), a hepatocyte-derived secreted factor, in both patients with MASH and mice fed a fast-food diet (FFD). KC-mediated hepatic inflammation, most notably IL-1β, led to the transcriptional inhibition of A1AT by HNF4α. In quintuple Serpina1a–e knockout mice, ablation of A1AT worsened MASH through increased activity of proteinase 3 (PR3), a proinflammatory protease produced by F4/80hi/CD11blow/TIM4−/CCR2+ monocyte-derived KCs (MoKCs). Conversely, A1AT restoration or PR3 inhibition mitigated MASH progression. A PR3-bound cytokine array identified IL-32 as a key factor associated with MASH. Combining IL-32 with SERPINA1, the gene encoding A1AT, synergistically predicted patients at risk of MASH through univariate logistic regression analysis. Furthermore, in vivo overexpression of IL-32γ alleviated MASH induced by FFD. However, additional knockout of A1AT increased PR3 activity, consequently abolishing the anti-MASH effects of IL-32γ. Blocking PR3-mediated IL-32γ cleavage via the V104A mutation sustained its protective actions, while the PR3-cleaved C-terminal fragment activated KCs. Additionally, after cleavage, the antifibrogenic effect of IL-32γ is lost, resulting in a failure to prevent the activation of hepatic stellate cells. This study highlights the critical role of hepatocyte-derived A1AT in the PR3/IL-32γ axis during MASH development. Strategies to correct A1AT dysregulation, such as A1AT supplementation or PR3 inhibition with sivelestat, may offer protection against the development and progression of MASH and fibrosis. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver failure worldwide. Researchers are trying to understand how it progresses to more severe conditions such as metabolic dysfunction-associated steatohepatitis (MASH). This study focuses on a protein called alpha-1-antitrypsin, which is important for liver health. The researchers used mice and human samples to study the role of A1AT in liver disease. They found that A1AT levels are lower in people and mice with MASLD, which leads to increased inflammation and liver damage. They also discovered that a protein called proteinase 3 becomes more active when A1AT is low, worsening the condition. By experimenting with mice, they showed that increasing A1AT or blocking PR3 can reduce liver damage. This suggests new treatment possibilities for MASH. The study concludes that targeting the A1AT/PR3 pathway could help manage liver disease progression. 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 2","pages":"450-465"},"PeriodicalIF":9.5,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01408-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411401","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}
Pub Date : 2025-02-10DOI: 10.1038/s12276-025-01399-z
Hyun Jin Kim, Sangjun Lee, Gyu Hyun Kim, Kibong Sung, Taesik Yoo, Jung Hyun Pyo, Hee-Jung Jo, Sanghyeon Lee, Hyun-Young Lee, Jung Hoon Jung, Kea Joo Lee, Joung-Hun Kim
Psychostimulants, including cocaine, elicit stereotyped, addictive behaviors. The reemergence of silent synapses containing only NMDA-type glutamate receptors is a critical mediator of addiction memory and seeking behaviors. Despite the predominant abundance of GluN2B-containing NMDA-type glutamate receptors in silent synapses, their operational mechanisms are not fully understood. Here, using conditional depletion/deletion of GluN2B in D1-expressing accumbal medium spiny neurons, we examined the synaptic and behavioral actions that silent synapses incur after repeated exposure to cocaine. GluN2B ablation reduces the proportion of silent synapses, but some of them can persist by substitution with GluN2C, which drives the aberrantly facilitated synaptic incorporation of calcium-impermeable AMPA-type glutamate receptors (AMPARs). The resulting precocious maturation of silent synapses impairs addiction memory but increases locomotor activity, both of which can be normalized by the blockade of calcium-impermeable AMPAR trafficking. Collectively, GluN2B supports the competence of cocaine-induced silent synapses to specify the subunit composition of AMPARs and thereby the expression of addiction memory and related behaviors. Cocaine creates ‘silent synapses’, immature brain connections lacking AMPA receptors. Researchers studied mice with GluN2B, a key protein in these synapses, which was selectively removed from specific brain cells. Using genetic tools and electrophysiology, they found that GluN2B removal reduced silent synapses and weakened drug-related memory but unexpectedly increased drug sensitivity. The findings suggest that the removal of GluN2B leads to fewer silent synapses but GluN2B aids in their maturation by adding calcium-insensitive AMPA receptors. This highlights GluN2B’s crucial role in maintaining silent synapses, providing new insights into addiction memory and potential treatment strategies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"GluN2B-mediated regulation of silent synapses for receptor specification and addiction memory","authors":"Hyun Jin Kim, Sangjun Lee, Gyu Hyun Kim, Kibong Sung, Taesik Yoo, Jung Hyun Pyo, Hee-Jung Jo, Sanghyeon Lee, Hyun-Young Lee, Jung Hoon Jung, Kea Joo Lee, Joung-Hun Kim","doi":"10.1038/s12276-025-01399-z","DOIUrl":"10.1038/s12276-025-01399-z","url":null,"abstract":"Psychostimulants, including cocaine, elicit stereotyped, addictive behaviors. The reemergence of silent synapses containing only NMDA-type glutamate receptors is a critical mediator of addiction memory and seeking behaviors. Despite the predominant abundance of GluN2B-containing NMDA-type glutamate receptors in silent synapses, their operational mechanisms are not fully understood. Here, using conditional depletion/deletion of GluN2B in D1-expressing accumbal medium spiny neurons, we examined the synaptic and behavioral actions that silent synapses incur after repeated exposure to cocaine. GluN2B ablation reduces the proportion of silent synapses, but some of them can persist by substitution with GluN2C, which drives the aberrantly facilitated synaptic incorporation of calcium-impermeable AMPA-type glutamate receptors (AMPARs). The resulting precocious maturation of silent synapses impairs addiction memory but increases locomotor activity, both of which can be normalized by the blockade of calcium-impermeable AMPAR trafficking. Collectively, GluN2B supports the competence of cocaine-induced silent synapses to specify the subunit composition of AMPARs and thereby the expression of addiction memory and related behaviors. Cocaine creates ‘silent synapses’, immature brain connections lacking AMPA receptors. Researchers studied mice with GluN2B, a key protein in these synapses, which was selectively removed from specific brain cells. Using genetic tools and electrophysiology, they found that GluN2B removal reduced silent synapses and weakened drug-related memory but unexpectedly increased drug sensitivity. The findings suggest that the removal of GluN2B leads to fewer silent synapses but GluN2B aids in their maturation by adding calcium-insensitive AMPA receptors. This highlights GluN2B’s crucial role in maintaining silent synapses, providing new insights into addiction memory and potential treatment strategies. 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 2","pages":"436-449"},"PeriodicalIF":9.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01399-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392376","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}
Pub Date : 2025-02-10DOI: 10.1038/s12276-025-01395-3
Anusha Shanabag, Jessica Armand, Eugene Son, Hee Won Yang
Dysregulation of the cell cycle machinery, particularly the overactivation of cyclin-dependent kinases 4 and 6 (CDK4/6), is a hallmark of breast cancer pathogenesis. The introduction of CDK4/6 inhibitors has transformed the treatment landscape for hormone receptor-positive breast cancer by effectively targeting abnormal cell cycle progression. However, despite their initial clinical success, drug resistance remains a significant challenge, with no reliable biomarkers available to predict treatment response or guide strategies for managing resistant populations. Consequently, numerous studies have sought to investigate the mechanisms driving resistance to optimize the therapeutic use of CDK4/6 inhibitors and improve patient outcomes. Here we examine the molecular mechanisms regulating the cell cycle, current clinical applications of CDK4/6 inhibitors in breast cancer, and key mechanisms contributing to drug resistance. Furthermore, we discuss emerging predictive biomarkers and highlight potential directions for overcoming resistance and enhancing therapeutic efficacy. CDK4/6 inhibitors have revolutionized the treatment of hormone receptor-positive breast cancer by targeting abnormal cell growth. However, most patients eventually encounter drug resistance, and predicting responses remains a challenge. This Review delves into the mechanisms behind CDK4/6 inhibitor resistance and explores potential strategies to overcome it. The authors provide a comprehensive overview of the cell cycle and the role of CDK4/6 inhibitors, highlighting both genetic and nongenetic factors that drive resistance. Key insights reveal that mutations and alterations in signaling pathways significantly contribute to drug resistance, offering avenues for novel therapeutic targets. Moreover, the Review emphasizes the importance of biomarkers to better predict treatment outcomes. Understanding these resistance mechanisms is pivotal for developing advanced strategies to enhance therapy effectiveness and improve patient prognosis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Targeting CDK4/6 in breast cancer","authors":"Anusha Shanabag, Jessica Armand, Eugene Son, Hee Won Yang","doi":"10.1038/s12276-025-01395-3","DOIUrl":"10.1038/s12276-025-01395-3","url":null,"abstract":"Dysregulation of the cell cycle machinery, particularly the overactivation of cyclin-dependent kinases 4 and 6 (CDK4/6), is a hallmark of breast cancer pathogenesis. The introduction of CDK4/6 inhibitors has transformed the treatment landscape for hormone receptor-positive breast cancer by effectively targeting abnormal cell cycle progression. However, despite their initial clinical success, drug resistance remains a significant challenge, with no reliable biomarkers available to predict treatment response or guide strategies for managing resistant populations. Consequently, numerous studies have sought to investigate the mechanisms driving resistance to optimize the therapeutic use of CDK4/6 inhibitors and improve patient outcomes. Here we examine the molecular mechanisms regulating the cell cycle, current clinical applications of CDK4/6 inhibitors in breast cancer, and key mechanisms contributing to drug resistance. Furthermore, we discuss emerging predictive biomarkers and highlight potential directions for overcoming resistance and enhancing therapeutic efficacy. CDK4/6 inhibitors have revolutionized the treatment of hormone receptor-positive breast cancer by targeting abnormal cell growth. However, most patients eventually encounter drug resistance, and predicting responses remains a challenge. This Review delves into the mechanisms behind CDK4/6 inhibitor resistance and explores potential strategies to overcome it. The authors provide a comprehensive overview of the cell cycle and the role of CDK4/6 inhibitors, highlighting both genetic and nongenetic factors that drive resistance. Key insights reveal that mutations and alterations in signaling pathways significantly contribute to drug resistance, offering avenues for novel therapeutic targets. Moreover, the Review emphasizes the importance of biomarkers to better predict treatment outcomes. Understanding these resistance mechanisms is pivotal for developing advanced strategies to enhance therapy effectiveness and improve patient prognosis. 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 2","pages":"312-322"},"PeriodicalIF":9.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01395-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392379","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}
In recent years, the focus on human inflammation in research has increased, with aging-related inflammation widely recognized as a defining characteristic of aging. Inflammation is strongly correlated with mitochondrial dysfunction. Phosphoglycerate mutase family member 5 (PGAM5) is a novel modulator of mitochondrial homeostasis in response to mechanical stimulation. Here we review the structure and sublocalization of PGAM5, introduce its importance in programmed cell death and summarize its crucial roles in the development and progression of inflammatory diseases such as pneumonia, hepatitis, neuroinflammation and aging. Notably, PGAM5 has dual effects on controlling inflammation: distinct PGAM5-mediated mitochondrial functions exhibit cellular heterogeneity, leading to its dual functions in inflammation control. We therefore highlight the double-edged sword nature of PGAM5 as a potential critical regulator and innovative therapeutic target in inflammation. Finally, the challenges and future directions of the use of PGAM5, which has dual properties, as a target molecule in the clinic are discussed. This review provides crucial insights to guide the development of intelligent therapeutic strategies targeting PGAM5-specific regulation to treat intractable inflammatory conditions, as well as the potential extension of its broader application to other diseases to achieve more precise and effective treatment outcomes. This Review explores the role of the PGAM5 protein in inflammation and aging and investigates how PGAM5 affects mitochondrial function and inflammation. The authors review various experiments showing that PGAM5 can both promote and reduce inflammation by influencing processes such as mitochondrial fission and mitophagy, which are crucial for maintaining cell health. This research highlights that PGAM5 interacts with other proteins to regulate cell death and inflammation. The findings suggest that PGAM5 has a dual role: it can either worsen or alleviate inflammation depending on the context. This dual nature makes it a potential target for treating inflammatory diseases. Future research could focus on developing therapies that modulate PGAM5 activity to treat conditions such as arthritis or neurodegenerative diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The dual role of PGAM5 in inflammation","authors":"Yuxin Qi, Bhavana Rajbanshi, Ruihan Hao, Yifan Dang, Churong Xu, Wei Lu, Liming Dai, Bingjun Zhang, Xiaoling Zhang","doi":"10.1038/s12276-025-01391-7","DOIUrl":"10.1038/s12276-025-01391-7","url":null,"abstract":"In recent years, the focus on human inflammation in research has increased, with aging-related inflammation widely recognized as a defining characteristic of aging. Inflammation is strongly correlated with mitochondrial dysfunction. Phosphoglycerate mutase family member 5 (PGAM5) is a novel modulator of mitochondrial homeostasis in response to mechanical stimulation. Here we review the structure and sublocalization of PGAM5, introduce its importance in programmed cell death and summarize its crucial roles in the development and progression of inflammatory diseases such as pneumonia, hepatitis, neuroinflammation and aging. Notably, PGAM5 has dual effects on controlling inflammation: distinct PGAM5-mediated mitochondrial functions exhibit cellular heterogeneity, leading to its dual functions in inflammation control. We therefore highlight the double-edged sword nature of PGAM5 as a potential critical regulator and innovative therapeutic target in inflammation. Finally, the challenges and future directions of the use of PGAM5, which has dual properties, as a target molecule in the clinic are discussed. This review provides crucial insights to guide the development of intelligent therapeutic strategies targeting PGAM5-specific regulation to treat intractable inflammatory conditions, as well as the potential extension of its broader application to other diseases to achieve more precise and effective treatment outcomes. This Review explores the role of the PGAM5 protein in inflammation and aging and investigates how PGAM5 affects mitochondrial function and inflammation. The authors review various experiments showing that PGAM5 can both promote and reduce inflammation by influencing processes such as mitochondrial fission and mitophagy, which are crucial for maintaining cell health. This research highlights that PGAM5 interacts with other proteins to regulate cell death and inflammation. The findings suggest that PGAM5 has a dual role: it can either worsen or alleviate inflammation depending on the context. This dual nature makes it a potential target for treating inflammatory diseases. Future research could focus on developing therapies that modulate PGAM5 activity to treat conditions such as arthritis or neurodegenerative diseases. 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 2","pages":"298-311"},"PeriodicalIF":9.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01391-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392382","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}
Pub Date : 2025-02-05DOI: 10.1038/s12276-025-01407-2
Yingwei Li, Zhongshao Chen, Huimin Xiao, Yanling Liu, Chen Zhao, Ning Yang, Cunzhong Yuan, Shi Yan, Peng Li
Dysregulated alternative splicing has been closely linked to the initiation and progression of tumors. Nevertheless, the precise molecular mechanisms through which splicing factors regulate endometrial cancer progression are still not fully understood. This study demonstrated elevated expression of the splicing factor SNRPB in endometrial cancer samples. Furthermore, our findings indicate that high SNRPB expression is correlated with poor prognosis in patients with endometrial cancer. Functionally, SNRPB inhibition hindered the proliferative and metastatic capacities of endometrial cancer cells. Mechanistically, we revealed that SNRPB knockdown decreased POLD1 expression and that POLD1 intron 22 was retained after SNRPB silencing in endometrial cancer cells, as determined via RNA sequencing data analysis. The retained intron 22 of POLD1 created a premature termination codon, leading to the absence of amino acids 941–1,107 and the loss of the site of interaction with PCNA, which is essential for POLD1 enzyme activity. In addition, POLD1 depletion decreased the increase in the malignancy of endometrial cancer cells overexpressing SNRPB. Furthermore, miR-654-5p was found to bind directly to the 3′ untranslated region of SNRPB, resulting in SNRPB expression inhibition in endometrial cancer. Antisense oligonucleotide-mediated SNRPB inhibition led to a decrease in the growth capacity of a cell-derived xenograft model and a patient with endometrial cancer-derived xenograft model. Overall, SNRPB promotes the efficient splicing of POLD1 by regulating intron retention, ultimately contributing to high POLD1 expression in endometrial cancer. The oncogenic SNRPB–POLD1 axis is an interesting therapeutic target for endometrial cancer, and antisense oligonucleotide-mediated silencing of SNRPB may constitute a promising therapeutic approach for treating patients with endometrial cancer. Endometrial cancer is a common cancer in women, with rising cases linked to obesity. This study focuses on a protein called SNRPB, which is involved in RNA splicing. SNRPB is found in high levels in endometrial cancer and is linked to poor outcomes. Researchers used various methods, including bioinformatics and lab experiments, to study SNRPB’s role. They found that reducing SNRPB levels slowed cancer cell growth and spread. They also discovered that SNRPB affects another protein, POLD1, which is important for DNA replication and repair. Lowering SNRPB led to changes in POLD1 that hindered cancer progression. This study suggests that targeting SNRPB with antisense oligonucleotides, which are short DNA or RNA molecules designed to block specific genes, could be a promising treatment strategy. This approach could lead to new therapies for endometrial cancer in the future. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Targeting the splicing factor SNRPB inhibits endometrial cancer progression by retaining the POLD1 intron","authors":"Yingwei Li, Zhongshao Chen, Huimin Xiao, Yanling Liu, Chen Zhao, Ning Yang, Cunzhong Yuan, Shi Yan, Peng Li","doi":"10.1038/s12276-025-01407-2","DOIUrl":"10.1038/s12276-025-01407-2","url":null,"abstract":"Dysregulated alternative splicing has been closely linked to the initiation and progression of tumors. Nevertheless, the precise molecular mechanisms through which splicing factors regulate endometrial cancer progression are still not fully understood. This study demonstrated elevated expression of the splicing factor SNRPB in endometrial cancer samples. Furthermore, our findings indicate that high SNRPB expression is correlated with poor prognosis in patients with endometrial cancer. Functionally, SNRPB inhibition hindered the proliferative and metastatic capacities of endometrial cancer cells. Mechanistically, we revealed that SNRPB knockdown decreased POLD1 expression and that POLD1 intron 22 was retained after SNRPB silencing in endometrial cancer cells, as determined via RNA sequencing data analysis. The retained intron 22 of POLD1 created a premature termination codon, leading to the absence of amino acids 941–1,107 and the loss of the site of interaction with PCNA, which is essential for POLD1 enzyme activity. In addition, POLD1 depletion decreased the increase in the malignancy of endometrial cancer cells overexpressing SNRPB. Furthermore, miR-654-5p was found to bind directly to the 3′ untranslated region of SNRPB, resulting in SNRPB expression inhibition in endometrial cancer. Antisense oligonucleotide-mediated SNRPB inhibition led to a decrease in the growth capacity of a cell-derived xenograft model and a patient with endometrial cancer-derived xenograft model. Overall, SNRPB promotes the efficient splicing of POLD1 by regulating intron retention, ultimately contributing to high POLD1 expression in endometrial cancer. The oncogenic SNRPB–POLD1 axis is an interesting therapeutic target for endometrial cancer, and antisense oligonucleotide-mediated silencing of SNRPB may constitute a promising therapeutic approach for treating patients with endometrial cancer. Endometrial cancer is a common cancer in women, with rising cases linked to obesity. This study focuses on a protein called SNRPB, which is involved in RNA splicing. SNRPB is found in high levels in endometrial cancer and is linked to poor outcomes. Researchers used various methods, including bioinformatics and lab experiments, to study SNRPB’s role. They found that reducing SNRPB levels slowed cancer cell growth and spread. They also discovered that SNRPB affects another protein, POLD1, which is important for DNA replication and repair. Lowering SNRPB led to changes in POLD1 that hindered cancer progression. This study suggests that targeting SNRPB with antisense oligonucleotides, which are short DNA or RNA molecules designed to block specific genes, could be a promising treatment strategy. This approach could lead to new therapies for endometrial cancer in the future. 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 2","pages":"420-435"},"PeriodicalIF":9.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01407-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143257220","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}
Pub Date : 2025-02-03DOI: 10.1038/s12276-025-01390-8
Dong-Kyo Lee, Xian Jin, Poo-Reum Choi, Ying Cui, Xiangguo Che, Sihoon Lee, Keun Hur, Hyun-Ju Kim, Je-Yong Choi
Phospholipase C β (PLCβ) is involved in diverse biological processes, including inflammatory responses and neurogenesis; however, its role in bone cell function is largely unknown. Among the PLCβ isoforms (β1–β4), we found that PLCβ4 was the most highly upregulated during osteoclastogenesis. Here we used global knockout and osteoclast lineage-specific PLCβ4 conditional knockout (LysM-PLCβ4−/−) mice as subjects and demonstrated that PLCβ4 is a crucial regulator of receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation. The deletion of PLCβ4, both globally and in the osteoclast lineage, resulted in a significant reduction in osteoclast formation and the downregulation of osteoclast marker genes. Notably, male LysM-PLCβ4−/− mice presented greater bone mass and fewer osteoclasts in vivo than their wild-type littermates, without altered osteoblast function. Mechanistically, we found that PLCβ4 forms a complex with p38 mitogen-activated protein kinase (MAPK) and MAPK kinase 3 (MKK3) in response to RANKL-induced osteoclast differentiation, thereby modulating p38 activation. An immunofluorescence assay further confirmed the colocalization of PLCβ4 with p38 after RANKL exposure. Moreover, p38 activation rescued impaired osteoclast formation and restored the reduction in p38 phosphorylation caused by PLCβ4 deficiency. Thus, our findings reveal that PLCβ4 controls osteoclastogenesis via the RANKL-dependent MKK3–p38 MAPK pathway and that PLCβ4 may be a potential therapeutic candidate for bone diseases such as osteoporosis. Osteoclasts are cells that break down bone tissue, and their formation is crucial for bone health. This study explores the role of a protein called PLCβ4 in osteoclast development. Researchers found that PLCβ4 levels increase during osteoclast differentiation, suggesting its importance. The study used mice with specific gene modifications to understand PLCβ4’s role. The researchers used gene knockdown techniques and studied mice lacking PLCβ4 to observe changes in bone cells. They found that reducing PLCβ4 led to fewer osteoclasts and increased bone mass, especially in male mice. This suggests that PLCβ4 is vital for normal bone breakdown. The study concludes that PLCβ4 is crucial for osteoclast development by affecting a signaling pathway involving MKK3 and p38 MAPK. Understanding this process could lead to new treatments for bone diseases such as osteoporosis, where bone breakdown is excessive. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Phospholipase C β4 promotes RANKL-dependent osteoclastogenesis by interacting with MKK3 and p38 MAPK","authors":"Dong-Kyo Lee, Xian Jin, Poo-Reum Choi, Ying Cui, Xiangguo Che, Sihoon Lee, Keun Hur, Hyun-Ju Kim, Je-Yong Choi","doi":"10.1038/s12276-025-01390-8","DOIUrl":"10.1038/s12276-025-01390-8","url":null,"abstract":"Phospholipase C β (PLCβ) is involved in diverse biological processes, including inflammatory responses and neurogenesis; however, its role in bone cell function is largely unknown. Among the PLCβ isoforms (β1–β4), we found that PLCβ4 was the most highly upregulated during osteoclastogenesis. Here we used global knockout and osteoclast lineage-specific PLCβ4 conditional knockout (LysM-PLCβ4−/−) mice as subjects and demonstrated that PLCβ4 is a crucial regulator of receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation. The deletion of PLCβ4, both globally and in the osteoclast lineage, resulted in a significant reduction in osteoclast formation and the downregulation of osteoclast marker genes. Notably, male LysM-PLCβ4−/− mice presented greater bone mass and fewer osteoclasts in vivo than their wild-type littermates, without altered osteoblast function. Mechanistically, we found that PLCβ4 forms a complex with p38 mitogen-activated protein kinase (MAPK) and MAPK kinase 3 (MKK3) in response to RANKL-induced osteoclast differentiation, thereby modulating p38 activation. An immunofluorescence assay further confirmed the colocalization of PLCβ4 with p38 after RANKL exposure. Moreover, p38 activation rescued impaired osteoclast formation and restored the reduction in p38 phosphorylation caused by PLCβ4 deficiency. Thus, our findings reveal that PLCβ4 controls osteoclastogenesis via the RANKL-dependent MKK3–p38 MAPK pathway and that PLCβ4 may be a potential therapeutic candidate for bone diseases such as osteoporosis. Osteoclasts are cells that break down bone tissue, and their formation is crucial for bone health. This study explores the role of a protein called PLCβ4 in osteoclast development. Researchers found that PLCβ4 levels increase during osteoclast differentiation, suggesting its importance. The study used mice with specific gene modifications to understand PLCβ4’s role. The researchers used gene knockdown techniques and studied mice lacking PLCβ4 to observe changes in bone cells. They found that reducing PLCβ4 led to fewer osteoclasts and increased bone mass, especially in male mice. This suggests that PLCβ4 is vital for normal bone breakdown. The study concludes that PLCβ4 is crucial for osteoclast development by affecting a signaling pathway involving MKK3 and p38 MAPK. Understanding this process could lead to new treatments for bone diseases such as osteoporosis, where bone breakdown is excessive. 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 2","pages":"323-334"},"PeriodicalIF":9.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01390-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081915","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}
Pub Date : 2025-02-03DOI: 10.1038/s12276-025-01393-5
Hyun Min Jeon, Hae Sook Noh, Min-Gyu Jeon, Jin-Ho Park, Young-Sun Lee, Gyunghwa Seo, Yun-Hong Cheon, Mingyo Kim, Myung-Kwan Han, Jae-Yong Park, Sang-Il Lee
Fibroblast-like synoviocytes (FLSs), which are stromal cells that play key roles in rheumatoid arthritis (RA) pathophysiology, are characterized by a tumor-like phenotype and immunostimulatory actions. C2 domains in various proteins play roles in intracellular signaling and altering cellular characteristics, and some C2 domain-containing proteins exacerbate or alleviate certain malignant or inflammatory diseases. However, the roles of C2 domains in regulating the functions of RA FLSs remain unclear. Here we performed functional C2 domainomics with 144 C2 domain-containing viral vectors and identified the C2 domain of PLCη2 as a key regulator of RA FLSs. In mice, overexpressing PLCη2 or only its C2 domain PLCη2 (PLCη2_C2) diminished the proliferation, migration, invasion and inflammatory responses of RA FLSs, mitigating RA pathology; the absence of PLCη2 amplified these proinflammatory and destructive processes in RA FLSs in vivo. Mechanistically, PLCη2 and PLCη2_C2 participate in the pathological signaling of RA FLSs in a calcium-independent manner through protein–protein interactions. Specifically, PLCη2_C2 disrupted HRAS–RAF1 interactions, suppressing downstream signaling pathways, including the NF-κB, JAK–STAT and MAPK pathways. Collectively, these findings establish PLCη2 and PLCη2_C2 as novel inhibitory regulators in RA, suggesting promising therapeutic avenues for addressing FLS-driven disease mechanisms. Rheumatoid arthritis is a disease in which the immune system attacks the joints, causing pain and damage. Researchers are looking for new ways to treat RA by targeting specific cells in the joints called fibroblast-like synoviocytes. These cells behave like cancer cells and contribute to joint damage. Researchers studied a protein called PLCη2, which is less active in patients with RA. They used a method called high-throughput screening to find proteins that could be targeted to treat RA. They discovered that increasing PLCη2 levels in FLSs reduced their aggressive behavior and inflammation. The study involved experiments with human cells and mice. The researchers used viral vectors to increase PLCη2 in FLSs and observed reduced cell growth and increased cell death. They also found that PLCη2 interacts with another protein, HRAS, to block harmful signaling pathways. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The HRAS-binding C2 domain of PLCη2 suppresses tumor‐like synoviocytes and experimental arthritis in rheumatoid arthritis","authors":"Hyun Min Jeon, Hae Sook Noh, Min-Gyu Jeon, Jin-Ho Park, Young-Sun Lee, Gyunghwa Seo, Yun-Hong Cheon, Mingyo Kim, Myung-Kwan Han, Jae-Yong Park, Sang-Il Lee","doi":"10.1038/s12276-025-01393-5","DOIUrl":"10.1038/s12276-025-01393-5","url":null,"abstract":"Fibroblast-like synoviocytes (FLSs), which are stromal cells that play key roles in rheumatoid arthritis (RA) pathophysiology, are characterized by a tumor-like phenotype and immunostimulatory actions. C2 domains in various proteins play roles in intracellular signaling and altering cellular characteristics, and some C2 domain-containing proteins exacerbate or alleviate certain malignant or inflammatory diseases. However, the roles of C2 domains in regulating the functions of RA FLSs remain unclear. Here we performed functional C2 domainomics with 144 C2 domain-containing viral vectors and identified the C2 domain of PLCη2 as a key regulator of RA FLSs. In mice, overexpressing PLCη2 or only its C2 domain PLCη2 (PLCη2_C2) diminished the proliferation, migration, invasion and inflammatory responses of RA FLSs, mitigating RA pathology; the absence of PLCη2 amplified these proinflammatory and destructive processes in RA FLSs in vivo. Mechanistically, PLCη2 and PLCη2_C2 participate in the pathological signaling of RA FLSs in a calcium-independent manner through protein–protein interactions. Specifically, PLCη2_C2 disrupted HRAS–RAF1 interactions, suppressing downstream signaling pathways, including the NF-κB, JAK–STAT and MAPK pathways. Collectively, these findings establish PLCη2 and PLCη2_C2 as novel inhibitory regulators in RA, suggesting promising therapeutic avenues for addressing FLS-driven disease mechanisms. Rheumatoid arthritis is a disease in which the immune system attacks the joints, causing pain and damage. Researchers are looking for new ways to treat RA by targeting specific cells in the joints called fibroblast-like synoviocytes. These cells behave like cancer cells and contribute to joint damage. Researchers studied a protein called PLCη2, which is less active in patients with RA. They used a method called high-throughput screening to find proteins that could be targeted to treat RA. They discovered that increasing PLCη2 levels in FLSs reduced their aggressive behavior and inflammation. The study involved experiments with human cells and mice. The researchers used viral vectors to increase PLCη2 in FLSs and observed reduced cell growth and increased cell death. They also found that PLCη2 interacts with another protein, HRAS, to block harmful signaling pathways. 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 2","pages":"335-348"},"PeriodicalIF":9.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01393-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143081961","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}
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