{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:08:15Z","timestamp":1791227295848,"version":"4.1.0"},"reference-count":133,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences","award":["2025-I2M-KJ-018"],"award-info":[{"award-number":["2025-I2M-KJ-018"]}]},{"name":"Fundamental Research Funds for the Central Universities, Peking Union Medical College","award":["3332025164"],"award-info":[{"award-number":["3332025164"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Berberine (BBR), a protoberberine alkaloid with a long history of medicinal use, has consistently demonstrated benefits in glucose\u2013lipid metabolism and inflammatory balance across both preclinical and human studies. These diverse effects are not mediated by a single molecular target but by BBR\u2019s capacity to restore network coordination among metabolic, immune, and microbial systems. At the core of this regulation is an AMP-activated Protein Kinase (AMPK)-centered mechanistic hub, integrating signals from insulin and nutrient sensing, Sirtuin 1\/3 (SIRT1\/3)-mediated mitochondrial adaptation, and inflammatory pathways such as nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-\u03baB) and NOD-, LRR- and Pyrin Domain-containing Protein 3 (NLRP3). This hub is dynamically regulated by system-level inputs from the gut, mitochondria, and epigenome, which in turn strengthen intestinal barrier function, reshape microbial and bile-acid metabolites, improve redox balance, and potentially reverse the epigenetic imprint of metabolic stress. These interactions propagate through multi-organ axes, linking the gut, liver, adipose, and vascular systems, thus aligning local metabolic adjustments with systemic homeostasis. Within this framework, BBR functions as a negentropic modulator, reducing metabolic entropy by fostering a coordinated balance among these interconnected systems, thereby restoring physiological order. Combination strategies, such as pairing BBR with metformin, Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors, and agents targeting the microbiome or inflammation, have shown enhanced efficacy and substantial translational potential. Berberine ursodeoxycholate (HTD1801), an ionic-salt derivative of BBR currently in Phase III trials and directly compared with dapagliflozin, exemplifies the therapeutic promise of such approaches. Within the hub\u2013axis paradigm, BBR emerges as a systems-level modulator that recouples energy, immune, and microbial circuits to drive multi-organ remodeling.<\/jats:p>","DOI":"10.3390\/ijms27020747","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T10:25:23Z","timestamp":1768213523000},"page":"747","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Berberine: A Negentropic Modulator for Multi-System Coordination"],"prefix":"10.3390","volume":"27","author":[{"given":"Xiaolian","family":"Tian","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingbo","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"He","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanbin","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiandong","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"},{"name":"Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7186-5251","authenticated-orcid":false,"given":"Lulu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/S2213-8587(19)30084-1","article-title":"Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: A position statement","volume":"7","author":"Neeland","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"155919","DOI":"10.1016\/j.metabol.2024.155919","article-title":"Obesity and dyslipidemia in early life: Impact on cardiometabolic risk","volume":"156","author":"Zeljkovic","year":"2024","journal-title":"Metabolism"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"108593","DOI":"10.1016\/j.pharmthera.2024.108593","article-title":"Berberine prevents NAFLD and HCC by modulating metabolic disorders","volume":"254","author":"Lin","year":"2024","journal-title":"Pharmacol. 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