{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:04:46Z","timestamp":1790787886188,"version":"4.1.0"},"reference-count":111,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T00:00:00Z","timestamp":1764028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Obesity and its related disorders, such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD), represent a worldwide health challenge, which is driven primarily by the dysfunction of the adipose tissue\u2013gut\u2013liver axis. This article compiles mechanistic and translational data on curcumin and its analogs as multi-organ regulators targeting this axis. Curcumin plays a pleiotropic role by modulating adipogenesis, lipid metabolism, inflammation, fibrosis, and thermogenic remodeling in adipose tissue, tailoring gut microbial diversity, gut barrier integrity, and metabolic endotoxemia. Curcumin in the liver attenuates steatosis, oxidation, and fibrosis by inhibiting lipogenesis, increasing \u03b2-oxidation, and modulating the NF-\u03baB and TGF-\u03b2 signal pathways. These actions result in overall systemic insulin sensitivity and energy balance. On the contrary, the clinical application of curcumin is restricted due to its low solubility, instability, and poor bioavailability. New formulations (nanoparticles\/liposomes\/micelles) together with structurally enhanced analogs such as tetrahydrocurcumin and monocarbonyl analogs (C66, B2BrBC) exhibited superior pharmacokinetic and tissue-targeting properties in preclinical models. Pilot and randomized clinical trials suggest that curcumin supplementation enhances glucose and lipid metabolism, reduces liver fat content, and modulates inflammatory markers; however, results across studies remain heterogeneous. Large, high-quality multicenter trials using rigorously standardized, bioavailable curcumin formulations are still required to reliably establish the efficacy and safety of curcumin in metabolic diseases. Next steps involve comparing curcumin analogs, conducting multi-omics analyses to understand host\u2013microbiota\u2013organ crosstalk, and determining cooperative approaches with lifestyle and pharmacological interventions. Taken together, curcumin and its next-generation derivatives may offer a novel therapeutic approach to intervene in the adipose tissue\u2013gut\u2013liver axis for the treatment of obesity-related metabolic diseases.<\/jats:p>","DOI":"10.3390\/ph18121791","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T15:29:47Z","timestamp":1764084587000},"page":"1791","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Curcumin and Tetrahydrocurcumin as Multi-Organ Modulators of the Adipose Tissue\u2013Gut\u2013Liver Axis: Mechanistic Insights, Therapeutic Potential, and Translational Challenges"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2519-5762","authenticated-orcid":false,"given":"Marina","family":"Konaktchieva","sequence":"first","affiliation":[{"name":"Gastroenterology Department, Military Medical Academy, Sofia Center, Ul. \u201cSveti Georgi Sofiyski\u201d 3, 1606 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5942-1622","authenticated-orcid":false,"given":"Radoslav","family":"Stojchevski","sequence":"additional","affiliation":[{"name":"Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA"},{"name":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"},{"name":"Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4498-7359","authenticated-orcid":false,"given":"Nikola","family":"Hadzi-Petrushev","sequence":"additional","affiliation":[{"name":"Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2759-7981","authenticated-orcid":false,"given":"Hristo","family":"Gagov","sequence":"additional","affiliation":[{"name":"Department of Animal and Human Physiology, Faculty of Biology, Sofia University \u201cSt. Kliment Ohridski\u201d, 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7981-4506","authenticated-orcid":false,"given":"Rositza","family":"Konakchieva","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Faculty of Biology, Sofia University \u201cSt. Kliment Ohridski\u201d, 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vadim","family":"Mitrokhin","sequence":"additional","affiliation":[{"name":"Department of Fundamental and Applied Physiology, Russian States Medical University, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gjoko","family":"Kungulovski","sequence":"additional","affiliation":[{"name":"Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. 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Cyril and Methodius University, 1000 Skopje, North Macedonia"},{"name":"Department of Fundamental and Applied Physiology, Russian States Medical University, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4479-6448","authenticated-orcid":false,"given":"Dimiter","family":"Avtanski","sequence":"additional","affiliation":[{"name":"Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA"},{"name":"Donald and Barbara Zucker School of Medicine at Hofstra\/Northwell, Hempstead, NY 11549, USA"},{"name":"Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,25]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2024). Obesity and Overweight\u2013Key Facts, World Health Organization. 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