{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:53:04Z","timestamp":1791553984023,"version":"4.3.4"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2021R1A6A1A03044296"],"award-info":[{"award-number":["NRF-2021R1A6A1A03044296"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-202400340550"],"award-info":[{"award-number":["NRF-202400340550"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2022-NR071138"],"award-info":[{"award-number":["RS-2022-NR071138"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>G-protein-coupled receptor 41 (GPR41\/FFAR3) functions as a crucial metabolic sensor of gut microbiota-derived short-chain fatty acids (SCFAs). However, the precise mechanisms by which GPR41 suppresses metabolic endotoxemia caused by translocation of gut-derived lipopolysaccharide (LPS) into the circulation remain unclear. In this study, we investigated the protective effects of AR420626 (AR), a selective GPR41 agonist, against endotoxemia using RAW 264.7 macrophages to mimic an endotoxin stress environment. Our results showed that AR-induced activation of GPR41 significantly suppressed the production of nitric oxide (NO) and interleukin-6 (IL-6), key pro-inflammatory mediators implicated in the pathogenesis of endotoxemia, through inhibition of the nuclear factor kappa B (NF-\u03baB) signaling pathway. In addition, AR-mediated GPR41 activation significantly reduced the expression of monocyte chemoattractant protein-1 (MCP-1) and inducible nitric oxide synthase (iNOS). These protective effects were mechanistically linked to enhanced autophagic activity, as evidenced by increased conversion of LC3-I to LC3-II. Importantly, pharmacological inhibition of autophagy abolished the ability of AR to suppress NF-\u03baB activation, suggesting that the GPR41-autophagy axis is essential for preserving macrophage homeostasis against LPS-induced endotoxemia damage. Furthermore, GPR41 knockdown markedly abrogated the AR-mediated regulation of iNOS, phosphorylated NF-\u03baB, and p62 under LPS stimulation, confirming that these protective effects are specifically mediated through GPR41. These results suggest that pharmacological activation of GPR41 to enhance autophagy may represent a novel therapeutic strategy for the treatment of endotoxemia.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00135","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:01:52Z","timestamp":1789416112000},"page":"2746-2757","source":"Crossref","is-referenced-by-count":0,"title":["G-Protein-Coupled\nReceptor 41 (GPR41) as a\nTherapeutic Target for Metabolic Endotoxemia: Mechanistic Insights\ninto AR420626-Induced Autophagy and Nuclear Factor kappa B (NF-\u03baB)\nSuppression"],"prefix":"10.1021","volume":"9","author":[{"given":"Do-Hyung","family":"Lee","sequence":"first","affiliation":[{"name":"Chung-Ang University , , 84 Heukseok-ro, Dongjak , ,","place":["Seoul, Republic of Korea, 06974"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Young","family":"Chun","sequence":"additional","affiliation":[{"name":"Chung-Ang University , , 84 Heukseok-ro, Dongjak , ,","place":["Seoul, Republic of Korea, 06974"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8461-8910","authenticated-orcid":true,"given":"Hun Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Chung-Ang University , , 84 Heukseok-ro, Dongjak , ,","place":["Seoul, Republic of Korea, 06974"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4566-6573","authenticated-orcid":true,"given":"Kyungsoo","family":"Oh","sequence":"additional","affiliation":[{"name":"Chung-Ang University , , 84 Heukseok-ro, Dongjak , ,","place":["Seoul, Republic of Korea, 06974"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"2026100909104517600_cit1","doi-asserted-by":"publisher","first-page":"e20","DOI":"10.1161\/CIRCRESAHA.124.325770","article-title":"Gut Microbiota\nMetabolites Sensed by Host GPR41\/43 Protect Against Hypertension","volume":"136","author":"Muralitharan","year":"2025","journal-title":"Circ. Res."},{"key":"2026100909104517600_cit2","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/s41575-019-0258-z","article-title":"Gut microbiota-derived metabolites\nas key actors in inflammatory\nbowel disease","volume":"17","author":"Lavelle","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"2026100909104517600_cit3","doi-asserted-by":"publisher","first-page":"277","DOI":"10.3389\/fimmu.2019.00277","article-title":"Short Chain Fatty Acids (SCFAs)-Mediated\nGut Epithelial and Immune Regulation and Its Relevance for Inflammatory\nBowel Diseases","volume":"10","author":"Parada Venegas","year":"2019","journal-title":"Front. Immunol."},{"key":"2026100909104517600_cit4","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/B978-0-12-800100-4.00003-9","article-title":"The role of short-chain\nfatty acids in health and disease","volume":"121","author":"Tan","year":"2014","journal-title":"Adv. Immunol."},{"key":"2026100909104517600_cit5","doi-asserted-by":"publisher","first-page":"111","DOI":"10.3389\/fendo.2012.00111","article-title":"Short-chain\nfree fatty acid receptors FFA2\/GPR43 and FFA3\/GPR41 as new potential\ntherapeutic targets","volume":"3","author":"Ulven","year":"2012","journal-title":"Front. Endocrinol."},{"key":"2026100909104517600_cit6","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1038\/nature08530","article-title":"Regulation of inflammatory\nresponses by gut microbiota and chemoattractant receptor GPR43","volume":"461","author":"Maslowski","year":"2009","journal-title":"Nature"},{"key":"2026100909104517600_cit7","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.3390\/cells14221823","article-title":"Valeric Acid: A Gut-Derived\nMetabolite as a Potential Epigenetic Modulator of Neuroinflammation\nin the Gut\u2013Brain Axis","volume":"14","author":"Paciolla","year":"2025","journal-title":"Cells"},{"key":"2026100909104517600_cit8","doi-asserted-by":"publisher","first-page":"28","DOI":"10.3389\/fimmu.2016.00028","article-title":"GPR41 and GPR43\nin Obesity and Inflammation \u2013\nProtective or Causative?","volume":"7","author":"Ang","year":"2016","journal-title":"Front. Immunol."},{"key":"2026100909104517600_cit9","unstructured":"Leonard, J. N., Chu, Z. L., Bruce, M. A., Boatman, P. D.\n          GPR41 and modulators\nthereof for the treatment of insulin-related disorders. U.S. Patent US20080200508A1, 2008."},{"key":"2026100909104517600_cit10","doi-asserted-by":"publisher","first-page":"3552","DOI":"10.1210\/en.2013-1142","article-title":"GPR41\/FFAR3 and\nGPR43\/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine\ncells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes","volume":"154","author":"N\u00f8hr","year":"2013","journal-title":"Endocrinology"},{"key":"2026100909104517600_cit11","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.13157","article-title":"Free fatty acid\nreceptor 3 activation suppresses neurogenic motility in rat proximal\ncolon","volume":"30","author":"Kaji","year":"2018","journal-title":"Neurogastroenterol. Motil."},{"key":"2026100909104517600_cit12","doi-asserted-by":"publisher","DOI":"10.1177\/1758835920913432","article-title":"AR420626, a selective\nagonist of GPR41\/FFA3, suppresses growth of hepatocellular carcinoma\ncells by inducing apoptosis via HDAC inhibition","volume":"12","author":"Mikami","year":"2020","journal-title":"Ther. Adv. Med. Oncol."},{"key":"2026100909104517600_cit13","doi-asserted-by":"publisher","first-page":"1871","DOI":"10.1002\/oby.23786","article-title":"G\u03b1i-coupled\nGPR41 activation\nincreases Ca2+ influx in C2C12 cells and shows a therapeutic effect\nin diabetic animals","volume":"31","author":"Lee","year":"2023","journal-title":"Obesity"},{"key":"2026100909104517600_cit14","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.111428","article-title":"Free fatty\nacid 3 receptor agonist\nAR420626 reduces allergic responses in asthma and eczema in mice","volume":"127","author":"Lee","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"2026100909104517600_cit15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.594150","article-title":"Role of Metabolic Endotoxemia in\nSystemic Inflammation\nand Potential Interventions","volume":"11","author":"Mohammad","year":"2021","journal-title":"Front. Immunol."},{"key":"2026100909104517600_cit16","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41392-024-01757-9","article-title":"NF-\u03baB in biology\nand targeted therapy: new insights and translational implications","volume":"9","author":"Guo","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"2026100909104517600_cit17","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/S0898-6568(00)00149-2","article-title":"LPS induction of gene expression\nin human monocytes","volume":"13","author":"Guha","year":"2001","journal-title":"Cell. Signal."},{"key":"2026100909104517600_cit18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1471-2172-8-1","article-title":"Transcriptional\nprofiling of the LPS induced NF-kappaB response in macrophages","volume":"8","author":"Sharif","year":"2007","journal-title":"BMC Immunol."},{"key":"2026100909104517600_cit19","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.3390\/ijms24021644","article-title":"Characterization\nof Lipopolysaccharide Effects on LRRK2 Signaling in RAW Macrophages","volume":"24","author":"Oun","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"2026100909104517600_cit20","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/nature09782","article-title":"Autophagy in immunity and inflammation","volume":"469","author":"Levine","year":"2011","journal-title":"Nature"},{"key":"2026100909104517600_cit21","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1038\/s41419-023-06154-8","article-title":"Autophagy: Regulator\nof cell death","volume":"14","author":"Liu","year":"2023","journal-title":"Cell Death Dis."},{"key":"2026100909104517600_cit22","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1093\/ibd\/izaf279","article-title":"The Role of\nAutophagy in Inflammatory Diseases: Challenges and Therapeutic Potential","volume":"32","author":"Mu\u0301nera-Rodri\u0301guez","year":"2026","journal-title":"Inflamm. Bowel Dis."},{"key":"2026100909104517600_cit23","doi-asserted-by":"publisher","first-page":"5720","DOI":"10.1093\/emboj\/19.21.5720","article-title":"LC3, a mammalian\nhomologue of yeast Apg8p, is localized in autophagosome membranes\nafter processing","volume":"19","author":"Kabeya","year":"2000","journal-title":"EMBO J."},{"key":"2026100909104517600_cit24","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/S0076-6879(08)03612-4","article-title":"Monitoring autophagic\ndegradation\nof p62\/SQSTM1","volume":"452","author":"Bj\u00f8rk\u00f8y","year":"2009","journal-title":"Methods Enzymol."},{"key":"2026100909104517600_cit25","doi-asserted-by":"publisher","first-page":"24131","DOI":"10.1074\/jbc.M702824200","article-title":"p62\/SQSTM1 binds directly to Atg8\/LC3\nto facilitate\ndegradation of ubiquitinated protein aggregates by autophagy","volume":"282","author":"Pankiv","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2026100909104517600_cit26","doi-asserted-by":"publisher","first-page":"3151","DOI":"10.1111\/bph.16345","article-title":"G protein-coupled receptor-mediated\nautophagy in health and disease","volume":"182","author":"O\u0308z-Arslan","year":"2025","journal-title":"Br. J. Pharmacol."},{"key":"2026100909104517600_cit27","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.tem.2014.03.006","article-title":"G protein-coupled\nreceptors and the regulation of autophagy","volume":"25","author":"Wauson","year":"2014","journal-title":"Trends\nEndocrinol. Metab."},{"key":"2026100909104517600_cit28","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.202100669","article-title":"Garcinia Cambogia\nImproves High-Fat\nDiet-Induced Glucose Imbalance by Enhancing Calcium\/CaMKII\/AMPK\/GLUT4-Mediated\nGlucose Uptake in Skeletal Muscle","volume":"66","author":"Han","year":"2022","journal-title":"Mol. Nutr.\nFood Res."},{"key":"2026100909104517600_cit29","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.jss.2007.12.758","article-title":"Lipopolysaccharide-stimulated\nRAW 264.7 macrophage inducible nitric oxide synthase and nitric oxide\nproduction is decreased by an omega-3 fatty acid lipid emulsion","volume":"149","author":"Aldridge","year":"2008","journal-title":"J. Surg. Res."},{"key":"2026100909104517600_cit30","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s42269-022-00747-7","article-title":"Effects of co-incubation of LPS-stimulated\nRAW 264.7 macrophages\non leptin production by 3T3-L1 adipocytes: a method for co-incubating\ndistinct adipose tissue cell lines","volume":"46","author":"Caldari-Torres","year":"2022","journal-title":"Bull. Natl.\nRes. Cent."},{"key":"2026100909104517600_cit31","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116735","article-title":"GPR41 and\nGPR43: From development\nto metabolic regulation","volume":"175","author":"Lee","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"2026100909104517600_cit32","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1053\/j.gastro.2013.04.056","article-title":"Short-chain fatty acids activate\nGPR41 and GPR43 on\nintestinal epithelial cells to promote inflammatory responses in mice","volume":"145","author":"Kim","year":"2013","journal-title":"Gastroenterology"},{"key":"2026100909104517600_cit33","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1038\/nm.3444","article-title":"Gut microbiota\nmetabolism of dietary fiber influences allergic airway disease and\nhematopoiesis","volume":"20","author":"Trompette","year":"2014","journal-title":"Nat. Med."},{"key":"2026100909104517600_cit34","doi-asserted-by":"publisher","DOI":"10.1111\/nmo.13157","article-title":"Free fatty acid\nreceptor 3 activation suppresses neurogenic motility in rat proximal\ncolon","volume":"30","author":"Kaji","year":"2018","journal-title":"Neurogastroenterol. Motil."},{"key":"2026100909104517600_cit35","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.cell.2009.04.020","article-title":"A Unifying Model\nfor the Selective Regulation of Inducible\nTranscription By CpG Islands and Nucleosome Remodeling","volume":"138","author":"Ramirez-Carrozzi","year":"2009","journal-title":"Cell"},{"key":"2026100909104517600_cit36","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1042\/EBC20240011","article-title":"CaMKK2: bridging\nthe gap between Ca2+ signaling and energy-sensing","volume":"68","author":"McAloon","year":"2024","journal-title":"Essays Biochem."},{"key":"2026100909104517600_cit37","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.1015500","article-title":"Role of AMPK in autophagy","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Physiol."},{"key":"2026100909104517600_cit38","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1007\/s00109-011-0748-0","article-title":"AMP-activated\nprotein kinase inhibits\nNF-\u03baB signaling and inflammation: impact on healthspan and lifespan","volume":"89","author":"Salminen","year":"2011","journal-title":"J. Mol. Med."},{"key":"2026100909104517600_cit39","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.3390\/cells8101255","article-title":"iNOS Interacts with\nAutophagy Receptor p62 and is Degraded\nby Autophagy in Macrophages","volume":"8","author":"Wang","year":"2019","journal-title":"Cells"},{"key":"2026100909104517600_cit40","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s40169-017-0154-5","article-title":"Autophagy\nand inflammation","volume":"6","author":"Qian","year":"2017","journal-title":"Clin. Transl. Med."},{"key":"2026100909104517600_cit41","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1038\/nature07383","article-title":"Loss of the autophagy\nprotein Atg16L1 enhances endotoxin-induced IL-1beta production","volume":"456","author":"Saitoh","year":"2008","journal-title":"Nature"},{"key":"2026100909104517600_cit42","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.cca.2007.01.026","article-title":"Adiponectin as an anti-inflammatory factor","volume":"380","author":"Ouchi","year":"2007","journal-title":"Clin. Chim. Acta"},{"key":"2026100909104517600_cit43","doi-asserted-by":"publisher","first-page":"3050","DOI":"10.3390\/biomedicines13123050","article-title":"Canonical\nNF-\u03baB Pathway as a Central Regulator of Obesity-Associated Inflammation:\nA Narrative Review","volume":"13","author":"Petrascu","year":"2025","journal-title":"Biomedicines"}],"container-title":["ACS Pharmacology &amp; Translational\nScience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsptsci.6c00135","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/10\/2746\/68505349\/acsptsci.6c00135.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article-pdf\/9\/10\/2746\/68505349\/acsptsci.6c00135.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:32:04Z","timestamp":1791552724000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aptsfn\/article\/9\/10\/2746\/5429653\/G-Protein-Coupled-Receptor-41-GPR41-as-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,14]]},"references-count":43,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,9,14]]},"published-print":{"date-parts":[[2026,10,9]]}},"URL":"https:\/\/doi.org\/10.1021\/acsptsci.6c00135","relation":{},"ISSN":["2575-9108"],"issn-type":[{"value":"2575-9108","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,14]]}}}