{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:02:24Z","timestamp":1791291744203,"version":"4.1.0"},"reference-count":133,"publisher":"American Chemical Society (ACS)","issue":"19","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\/501100007937","name":"Peking University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007937","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021187","name":"Beijing National Laboratory for Molecular Sciences","doi-asserted-by":"publisher","award":["BNLMS-CXXM-202106"],"award-info":[{"award-number":["BNLMS-CXXM-202106"]}],"id":[{"id":"10.13039\/501100021187","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["BX20250151"],"award-info":[{"award-number":["BX20250151"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22193073"],"award-info":[{"award-number":["22193073"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22337002"],"award-info":[{"award-number":["22337002"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22550007"],"award-info":[{"award-number":["22550007"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chinese Institutes for Medical Research, Beijing","award":["CX23YZ18"],"award-info":[{"award-number":["CX23YZ18"]}]},{"name":"New Cornerstone Science Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Conspectus<\/jats:title>\n                  <jats:p>Bile acids are a class of cholesterol-derived metabolites that have long been recognized for their essential roles in dietary lipid absorption and cholesterol homeostasis. Over the past two decades, however, bile acids have emerged as crucial signaling molecules that regulate diverse physiological and pathological processes, including metabolism, inflammation, immunity, host\u2013microbiota interactions, and liver diseases. Dysregulation of bile acid homeostasis has been implicated in a broad spectrum of human disorders, making bile acid signaling pathways attractive targets for therapeutic intervention. Despite substantial progress in identifying bile acid receptors and transporters, a fundamental challenge remains: how can we systematically decode the biological functions of structurally diverse bile acids and translate the knowledge into therapeutic opportunities?<\/jats:p>\n                  <jats:p>In this Account, we summarize our 10-year mechanism-driven research effort to address this challenge through an integrated translational chemical biology strategy that combines chemoproteomics, metabolomics, structural biology, and medicinal chemistry. We first developed chemoproteomic platforms to globally profile bile-acid-interacting proteins in mammalian cells and bacteria, revealing an extensive bile-acid interactome that extends beyond canonical receptors and transporters. These studies uncovered hundreds of candidate interactors and identified previously unrecognized bile-acid-sensing mechanisms in host cells and gut microbes, providing a systems-level framework for understanding bile acid biology.<\/jats:p>\n                  <jats:p>Building upon these discoveries, we focused on elucidating the molecular basis of cholestatic itch, a debilitating symptom frequently associated with liver diseases. We identified the G-protein-coupled receptor MRGPRX4 (hX4) as a human bile acid receptor mediating cholestatic pruritus and demonstrated that sulfated bile acids are key endogenous pruritogens that accumulate in patients with cholestasis. Through cryo-electron microscopy (cryo-EM), we determined the structure of hX4 in complex with a bile acid agonist and elucidated the molecular mechanism underlying receptor activation. These mechanistic insights revealed the critical role of the bile acid 3-hydroxyl group in receptor recognition and signaling.<\/jats:p>\n                  <jats:p>Importantly, a mechanistic understanding of bile acid signaling enabled the rational design of therapeutics. Guided by structural information, we developed a modified bile acid derivative that retains therapeutic efficacy for liver diseases while minimizing itch-related side effects. Furthermore, through high-throughput screening, medicinal chemistry optimization, structural analysis, and preclinical evaluation, we discovered HEP-50768, a potent inverse agonist of hX4 that has advanced toward clinical development for cholestatic itch. In parallel, we determined the cryo-EM structure of the bile acid transporter OST\u03b1\/\u03b2 and uncovered its transport mechanism, providing new insights into the regulation of bile acid homeostasis.<\/jats:p>\n                  <jats:p>Collectively, these studies illustrate how decoding bile acid function at the molecular level can uncover previously unrecognized biological mechanisms and accelerate drug discovery. We anticipate that the continued integration of chemical biology, structural biology, and translational pharmacology will enable the construction of a comprehensive functional atlas of bile acids and facilitate the development of next-generation therapeutics targeting bile acid signaling networks.<\/jats:p>","DOI":"10.1021\/acs.accounts.6c00477","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:01:36Z","timestamp":1789380096000},"page":"3134-3151","source":"Crossref","is-referenced-by-count":0,"title":["Decoding the\nBiological Function of Bile Acids for\nDrug Discovery"],"prefix":"10.1021","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2785-6971","authenticated-orcid":true,"given":"Jun","family":"Yang","sequence":"first","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0380-8035","authenticated-orcid":true,"given":"Xiaoguang","family":"Lei","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]},{"name":"Peking University , , ,","place":["Beijing, China, 100191"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"issue":"5","key":"2026100608062736600_cit1","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1021\/acscentsci.7b00134","article-title":"Chemoproteomic Profiling\nof Bile Acid Interacting Proteins","volume":"3","author":"Zhuang","year":"2017","journal-title":"ACS Cent.\nSci."},{"issue":"25","key":"2026100608062736600_cit2","doi-asserted-by":"publisher","first-page":"7164","DOI":"10.1016\/j.cell.2024.10.001","article-title":"Structure-guided\ndiscovery of bile acid derivatives for treating liver diseases without\ncausing itch","volume":"187","author":"Yang","year":"2024","journal-title":"Cell"},{"issue":"8104","key":"2026100608062736600_cit3","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/s41586-025-09934-8","article-title":"Structure and mechanism of the human bile acid transporter OST\u03b1\u2013OST\u03b2","volume":"651","author":"Wang","year":"2026","journal-title":"Nature"},{"key":"2026100608062736600_cit4","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-026-02195-0","article-title":"Development\nof a clinically viable MRGPRX4 inverse agonist for cholestatic itch\ntreatment","author":"Yang","year":"2026","journal-title":"Nat. Chem. Biol."},{"issue":"20","key":"2026100608062736600_cit5","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1007\/BF01731081","article-title":"U\u0308ber\ndie Cholagoge Wirkung der Dehydrocholsa\u0308ure beim Menschen","volume":"3","author":"Neubauer","year":"1924","journal-title":"Klin. Wochenschr."},{"issue":"11","key":"2026100608062736600_cit6","doi-asserted-by":"publisher","first-page":"bqac155","DOI":"10.1210\/endocr\/bqac155","article-title":"Bile Acids\u2500A Peek Into Their\nHistory and Signaling","volume":"163","author":"Nguyen","year":"2022","journal-title":"Endocrinology"},{"issue":"91","key":"2026100608062736600_cit7","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ade6924","article-title":"Sulfated bile acid is a host-derived\nligand for MAIT\ncells","volume":"9","author":"Ito","year":"2024","journal-title":"Sci. Immunol."},{"issue":"1","key":"2026100608062736600_cit8","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s40168-024-02011-8","article-title":"Microbiota\ngoverns host chenodeoxycholic acid glucuronidation to ameliorate bile\nacid disorder induced diarrhea","volume":"13","author":"Lin","year":"2025","journal-title":"Microbiome"},{"key":"2026100608062736600_cit9","doi-asserted-by":"publisher","first-page":"S21","DOI":"10.5604\/01.3001.0010.5672","article-title":"The Role of\nthe Gut Microbiota in Bile Acid Metabolism","volume":"16","author":"Rami\u0301rez-Pe\u0301rez","year":"2017","journal-title":"Ann. Hepatol."},{"issue":"2","key":"2026100608062736600_cit10","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1194\/jlr.R088989","article-title":"Microbial\nimpact on\ncholesterol and bile acid metabolism: current status and future prospects","volume":"60","author":"Kriaa","year":"2019","journal-title":"J. Lip. 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