BiomoleculesPub Date : 2025-02-18DOI: 10.3390/biom15020302
Norihiro Takekawa, Ayaka Yamaguchi, Koki Nishiuchi, Maria Uehori, Miki Kinoshita, Tohru Minamino, Katsumi Imada
{"title":"Sodium-Dependent Conformational Change in Flagellar Stator Protein MotS from <i>Bacillus subtilis</i>.","authors":"Norihiro Takekawa, Ayaka Yamaguchi, Koki Nishiuchi, Maria Uehori, Miki Kinoshita, Tohru Minamino, Katsumi Imada","doi":"10.3390/biom15020302","DOIUrl":"10.3390/biom15020302","url":null,"abstract":"<p><p>The bacterial flagellar motor consists of a rotor and stator units and is driven by ion flow through the stator. The activation of the ion flow is coupled with the anchoring of the stator units to the peptidoglycan layer by the stator B-subunit around the rotor. Gram-negative bacteria, such as <i>Salmonella</i> and <i>Vibrio</i>, change the conformation of the N-terminal helix of the periplasmic domain of the B-subunit to anchor the stator units. However, a recent high-speed atomic force microscopic study has suggested that the periplasmic domain of MotS, the stator B-subunit of the sodium (Na<sup>+</sup>)-driven stator of <i>Bacillus subtilis</i>, a gram-positive bacterium, unfolds at low external Na<sup>+</sup> concentrations and folds at high Na<sup>+</sup> concentrations to anchor the stator units. Here, we report the crystal structures of MotS<sub>68-242</sub>, a periplasmic fragment of MotS, from <i>B. subtilis</i> at high and low Na<sup>+</sup> concentrations. We also performed far-UV CD spectroscopic analysis of the wild-type MotS<sub>68-242</sub> and MotS<sub>78-242</sub> proteins and mutant variants of MotS<sub>68-242</sub> under high and low Na<sup>+</sup> concentrations and found that the N-terminal disordered region of MotS<sub>68-242</sub> shows a Na<sup>+</sup>-dependent coil-helix transition. We propose a mechanism of the Na<sup>+</sup>-dependent structural transition of Bs-MotS to anchor the stator units.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11853200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498881","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}
BiomoleculesPub Date : 2025-02-18DOI: 10.3390/biom15020303
Herbert Schulz, Fatima Abdelfattah, Anna Heinrich, Daniela Melnik, Viviann Sandt, Marcus Krüger, Markus Wehland, Per Hoffmann, José Luis Cortés-Sánchez, Matthias Evert, Katja Evert, Daniela Grimm
{"title":"Omics Investigations of Prostate Cancer Cells Exposed to Simulated Microgravity Conditions.","authors":"Herbert Schulz, Fatima Abdelfattah, Anna Heinrich, Daniela Melnik, Viviann Sandt, Marcus Krüger, Markus Wehland, Per Hoffmann, José Luis Cortés-Sánchez, Matthias Evert, Katja Evert, Daniela Grimm","doi":"10.3390/biom15020303","DOIUrl":"10.3390/biom15020303","url":null,"abstract":"<p><p>Prostate cancer (PC) is the most diagnosed cancer in males across the globe. Following the formation of metastasis, PC is linked to a notable decline in both prognosis and survival rates. Three-dimensional multicellular spheroids (MCSs) of a prostate adenocarcinoma cell line were generated in a three-day simulated microgravity environment (s-µ<i>g</i>) to serve as a model for metastasis and to derive transcriptional and epigenetic PC candidates from molecular biological changes. With an FDR of 10<sup>-3</sup>, we detected the most differentially expressed genes in the two comparisons' adherent cells (AD) to MCSs (N = 751 genes) and 1<i>g</i> control cells to MCSs (N = 662 genes). In these two comparisons, genes related to cell cycle, angiogenesis, cell adhesion, and extracellular space were consistently found to be significantly enriched in GO annotations. Furthermore, at a 5% FDR significance level, we were able to identify 11,090 genome-wide differentially methylated positions (DMPs) and one differentially methylated region in the <i>SRMS</i> gene in the 1<i>g</i> vs. AD comparison, as well as an additional 10,797 DMPs in the 1<i>g</i> vs. MCSs comparison. Finally, we identified five s-µ<i>g</i>-related positive enrichments of transcription factor binding sites for AR, IRF1, IRF2, STAT1, STAT2, and FOXJ3 close to the DMPs.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11853236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RORA Regulates Autophagy in Hair Follicle Stem Cells by Upregulating the Expression Level of the <i>Sqstm1</i> Gene.","authors":"Xuefei Zhao, Yanchun Xu, Shuqi Li, Suying Bai, Wei Zhang, Yu Zhang","doi":"10.3390/biom15020299","DOIUrl":"10.3390/biom15020299","url":null,"abstract":"<p><p>The hair coat is an adaptive evolutionary trait unique to mammals, aiding them in adapting to complex environmental challenges. Although some of the factors involved in regulating hair follicle development have been characterized, further in-depth research is still needed. Retinoic acid receptor-related orphan receptor alpha (RORA), as a member of the nuclear receptor family, is highly involved in the regulation of cellular states. Previous studies have shown that autophagy plays a significant role in hair follicle development. This study uses rat hair follicle stem cells (HFSCs) as a model to analyze the impact of RORA on the autophagy levels of HFSCs. Upon activation of RORA, autophagy indicators such as the LC3-II/LC3-I ratio and MDC staining significantly increased, suggesting an elevated level of autophagy in HFSCs. Following treatment with chloroquine, the LC3-II/LC3-I ratio, as well as the expression levels of BECN1 protein and SQSTM1 protein, were markedly elevated in the cells, indicating that the autophagic flux was unobstructed and ruling out the possibility that RORA activation impeded autophagy. Additionally, the level of the <i>Sqstm1</i> gene increased markedly after RORA activation promoted autophagy in the cells. We found that RORA regulates the transcription level of <i>Sqstm1</i> by binding to its promoter region. We believe that RORA activation significantly promotes the level of autophagy, particularly selective autophagy, in HFSCs, suggesting that RORA has the potential to become a new target for research on hair follicle development. This research provides a theoretical foundation for studies on hair follicle development and also offers new insights for the treatment of diseases such as alopecia.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11853448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498894","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}
BiomoleculesPub Date : 2025-02-17DOI: 10.3390/biom15020298
Ludmila A Alekseeva, Aleksandra V Sen'kova, Khetam Sounbuli, Innokenty A Savin, Marina A Zenkova, Nadezhda L Mironova
{"title":"Pulmozyme Ameliorates LPS-Induced Lung Fibrosis but Provokes Residual Inflammation by Modulating Cell-Free DNA Composition and Controlling Neutrophil Phenotype.","authors":"Ludmila A Alekseeva, Aleksandra V Sen'kova, Khetam Sounbuli, Innokenty A Savin, Marina A Zenkova, Nadezhda L Mironova","doi":"10.3390/biom15020298","DOIUrl":"10.3390/biom15020298","url":null,"abstract":"<p><p>Pulmonary fibrosis, a chronic progressive lung disorder, can be the result of previous acute inflammation-associated lung injury and involves a wide variety of inflammatory cells, causing the deposition of extracellular matrix (ECM) components in the lungs. Such lung injury is often associated with excessive neutrophil function and the formation of DNA networks in the lungs, which are also some of the most important factors for fibrosis development. Acute lung injury with subsequent fibrosis was initiated in C57Bl/6 mice by a single intranasal (i.n.) administration of LPS. Starting from day 14, human recombinant DNase I in the form of Pulmozyme for topical administration was instilled i.n. twice a week at a dose of 50 U/mouse. Cell-free DNA (cfDNA), DNase activity, and cell content were analyzed in blood serum and bronchoalveolar lavage fluid (BALF). Inflammatory and fibrotic changes in lung tissue were evaluated by histological analysis. The gene expression profile in spleen-derived neutrophils was analyzed by RT-qPCR. We demonstrated that Pulmozyme significantly reduced connective tissue expansion in the lungs. However, despite the reliable antifibrotic effect, complete resolution of inflammation in the respiratory system of mice treated with Pulmozyme was not achieved, possibly due to enhanced granulocyte recruitment and changes in the nuclear/mitochondrial cfDNA balance in the BALF. Moreover, Pulmozyme introduction caused the enrichment of the spleen-derived neutrophil population by those with an unusual phenotype, combining pro-inflammatory and anti-inflammatory features, which can also maintain lung inflammation. Pulmozyme can be considered a promising drug for lung fibrosis management; however, the therapy may be accompanied by residual inflammation.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11853346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498869","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}
BiomoleculesPub Date : 2025-02-17DOI: 10.3390/biom15020297
Xiayu Wang, Qian Du, Wanqian Li, Zhongyu Zou, Chikun Wang, Yan Zhou, Zhibin Hu, Yayun Gu, Feng Li
{"title":"Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of Spermatogenesis.","authors":"Xiayu Wang, Qian Du, Wanqian Li, Zhongyu Zou, Chikun Wang, Yan Zhou, Zhibin Hu, Yayun Gu, Feng Li","doi":"10.3390/biom15020297","DOIUrl":"10.3390/biom15020297","url":null,"abstract":"<p><p>PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that are almost exclusively expressed in germ cells to silence harmful transposons to maintain genome stability. PIWIL4 is guided by its associated piRNAs to transposable elements, where it recruits the DNA methylation apparatus and instructs de novo DNA methylation. Herein, we identified a missense variant of <i>PIWIL4</i> (c.805 C>T p.R269W) in two infertile males. Homozygous male mice carrying the orthologous knock-in variant displayed elevated transposable element expression and aberrant gene expression during the first wave of spermatogenesis, despite exhibiting normal sperm counts and morphology. Mechanistically, the mutated site altered the piRNA-binding ability of PIWIL4 and led to the derepression of endogenous LINE-1 elements. In summary, we identified a piRNA binding mutation in PIWIL4 that may be involved in human nonobstructive azoospermia.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498683","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}
BiomoleculesPub Date : 2025-02-17DOI: 10.3390/biom15020296
Sanghyun Ye, Seonju Lee, Seongsu Kang, Seung-Hyun Jun, Nae-Gyu Kang
{"title":"Improvement of Skin Condition Through RXR Alpha-Activating Materials.","authors":"Sanghyun Ye, Seonju Lee, Seongsu Kang, Seung-Hyun Jun, Nae-Gyu Kang","doi":"10.3390/biom15020296","DOIUrl":"10.3390/biom15020296","url":null,"abstract":"<p><p>Retinol is well-known anti-aging material in the cosmetics industry, owing to its proven superior efficacy both in vitro and in vivo. Despite its high efficacy, retinol is associated with limitations, such as skin irritation and its potential photodegradation. Retinol is converted into retinoid acid within cells, which then exerts a cellular response by activating both the retinoic acid receptor (RAR) and retinoid x receptor (RXR). Noting that RAR activity is associated with skin irritation and RXR activation alone can enhance skin-related indicators without inducing inflammation, we developed an alternative approach for skin anti-aging focusing solely on RXR activation. We found that combined treatment of andrographolide and <i>Bidens pilosa</i> extract successfully activated RXR alpha and enhanced <i>RXRA</i> gene expression. Moreover, we investigated their efficacy using dermal fibroblasts and keratinocytes and found that they enhanced the gene expression of extracellular matrix (ECM) proteins with anti-oxidant and anti-inflammation efficacies. Finally, in a human clinical trial, we confirmed that our materials successfully improved wrinkles in various areas, skin elasticity and hydration without causing irritating side effects. These findings highlight the potential of our RXR alpha-activating materials as an anti-wrinkle solution that avoids the typical side effects associated with retinol.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11853381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498778","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}
BiomoleculesPub Date : 2025-02-16DOI: 10.3390/biom15020294
Saeedeh Hajebi Khaniki, Farhad Shokoohi
{"title":"Data-Driven Identification of Early Cancer-Associated Genes via Penalized Trans-Dimensional Hidden Markov Models.","authors":"Saeedeh Hajebi Khaniki, Farhad Shokoohi","doi":"10.3390/biom15020294","DOIUrl":"10.3390/biom15020294","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a significant worldwide health problem due to its high prevalence, mortality rates, and frequent diagnosis at advanced stages. While diagnostic and therapeutic approaches have evolved, the underlying mechanisms driving CRC initiation and progression are not yet fully understood. Early detection is critical for improving patient survival, as initial cancer stages often exhibit epigenetic changes-such as DNA methylation-that regulate gene expression and tumor progression. Identifying DNA methylation patterns and key survival-related genes in CRC could thus enhance diagnostic accuracy and extend patient lifespans. In this study, we apply two of our recently developed methods for identifying differential methylation and analyzing survival using a sparse, finite mixture of accelerated failure time regression models, focusing on key genes and pathways in CRC datasets. Our approach outperforms two other leading methods, yielding robust findings and identifying novel differentially methylated cytosines. We found that CRC patient survival time follows a two-component mixture regression model, where genes <i>CDH11</i>, <i>EPB41L3</i>, and <i>DOCK2</i> are active in the more aggressive form of CRC, whereas <i>TMEM215</i>, <i>PPP1R14A</i>, <i>GPR158</i>, and <i>NAPSB</i> are active in the less aggressive form.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11853217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497439","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}
BiomoleculesPub Date : 2025-02-16DOI: 10.3390/biom15020295
Biljana Kosanovic Rajacic, Marina Sagud, Drazen Begic, Matea Nikolac Perkovic, Ana Kozmar, Dunja Rogic, Alma Mihaljevic Peles, Marija Bozicevic, Nela Pivac
{"title":"Increased Interleukin-6 Levels in Responders with Treatment-Resistant Depression After Bright Light Therapy.","authors":"Biljana Kosanovic Rajacic, Marina Sagud, Drazen Begic, Matea Nikolac Perkovic, Ana Kozmar, Dunja Rogic, Alma Mihaljevic Peles, Marija Bozicevic, Nela Pivac","doi":"10.3390/biom15020295","DOIUrl":"10.3390/biom15020295","url":null,"abstract":"<p><p>Treatment-resistant depression (TRD) remains a challenge despite the growing number of interventions. Peripheral interleukin-6 (IL-6) levels have repeatedly been associated with both the presence and response to different treatments in TRD. There is currently no information available on the effects of bright light therapy (BLT) on serum IL-6 levels. This study assessed the effects of BLT on serum IL-6 levels in TRD patients. Serum IL-6 was determined at two points in TRD patients-at baseline and after 4 weeks of BLT-and at a single point in the healthy controls. Depression severity was measured by the Hamilton Rating Scale for Depression (HAMD)-17 and the Montgomery-Åsberg Depression Rating Scale (MADRS). The study included 104 females, 54 diagnosed with TRD (median age 52.5) and 50 healthy controls (median age 44.5). At baseline, patients had higher IL-6 levels than the controls. BLT treatment reduced HAMD-17 and MADRS scores. Serum IL-6 levels were not significantly affected by the 4 weeks of BLT. However, when patients were divided according to treatment response, IL-6 levels were increased in responders to BLT. The neuroinflammatory mechanism may be involved in the etiopathogenesis and the treatment of TRD, while changes in serum IL-6 levels may be potential indicators of response to treatment.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lipid-siRNA Conjugates Targeting High PD-L1 Expression as Potential Novel Immune Checkpoint Inhibitors.","authors":"Rina Tansou, Takanori Kubo, Haruka Nishida, Yoshio Nishimura, Keichiro Mihara, Kazuyoshi Yanagihara, Toshio Seyama","doi":"10.3390/biom15020293","DOIUrl":"10.3390/biom15020293","url":null,"abstract":"<p><p>Programmed death 1 ligand (PD-L1), an important immune checkpoint molecule, is mainly expressed on cancer cells and has been shown to exert an immunosuppressive effect on T-cell function by binding to programmed cell death 1 (PD-1) expressed on T-cells. Recently, immune checkpoint inhibitors using antibody drugs such as nivolumab and atezolizumab have attracted attention. However, clinical challenges, including limitations to the scope of their application, are yet to be addressed. In this study, we developed a novel immune checkpoint inhibitor that targets PD-L1 using lipid-siRNA conjugates (lipid-siPDL1s). The inhibitory effect of lipid-siPDL1s on PD-L1 expression was evaluated and found to strongly suppress mRNA expression. Notably, lipid-siPDL1s exerted a significantly stronger effect than unmodified siPDL1. Interestingly, lipid-siPDL1s strongly inhibited PD-L1 expression despite cancer cell stimulation by interferon-gamma, which induced the overexpression of PD-L1 genes. These results strongly suggest that lipid-siPDL1s could be used as novel immune checkpoint inhibitors.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498837","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}
BiomoleculesPub Date : 2025-02-15DOI: 10.3390/biom15020291
Yun Yeong Cho, Soyeon Kim, Pankyung Kim, Min Jeong Jo, Song-E Park, Yiju Choi, Su Myung Jung, Hye Jin Kang
{"title":"G-Protein-Coupled Receptor (GPCR) Signaling and Pharmacology in Metabolism: Physiology, Mechanisms, and Therapeutic Potential.","authors":"Yun Yeong Cho, Soyeon Kim, Pankyung Kim, Min Jeong Jo, Song-E Park, Yiju Choi, Su Myung Jung, Hye Jin Kang","doi":"10.3390/biom15020291","DOIUrl":"10.3390/biom15020291","url":null,"abstract":"<p><p>G-protein coupled receptors (GPCRs), the largest family of integral membrane proteins, enable cells to sense and appropriately respond to the environment through mediating extracellular signaling to intercellular messenger molecules. GPCRs' pairing with a diverse array of G protein subunits and related downstream secondary messengers, combined with their ligand versatility-from conventional peptide hormone to numerous bioactive metabolites, allow GPCRs to comprehensively regulate metabolism and physiology. Consequently, GPCRs have garnered significant attention for their therapeutic potential in metabolic diseases. This review focuses on six GPCRs, GPR40, GPR120, GLP-1R, and ß-adrenergic receptors (ADRB1, ADRB2, and ADRB3), with GLP-1R recognized as a prominent regulator of system-level metabolism, while the roles of GPR40, GPR120 and ß-adrenergic receptors in central carbon metabolism and energy homeostasis are increasingly appreciated. Here, we discuss their physiological functions in metabolism, the current pharmacological landscape, and the intricacies of their signaling pathways via G protein and ß-arrestin activation. Additionally, we discuss the limitations of existing GPCR-targeted strategies for treating metabolic diseases and offer insights into future perspectives for advancing GPCR pharmacology.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"15 2","pages":""},"PeriodicalIF":4.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11852853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143498746","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}