{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T12:55:44Z","timestamp":1793105744726,"version":"4.5.0"},"reference-count":183,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Curcumin is widely recognized for its anti-inflammatory and antioxidant properties; however, this conventional framing obscures a broader, complex, and mechanistically diverse pharmacology. Here, we advance a refined perspective that situates curcumin within a hierarchical and multilayered architecture shaped by the dynamic interplay of intrinsic chemical reactivity, metabolic transformation and exposure, and microbial modulation. From this standpoint, curcumin functions as a network-level modulator, producing context-dependent outcomes rather than uniform or linear responses. Consequently, its biological influence extends well beyond traditional paradigms, engaging pathways involved in xenobiotic metabolism, membrane transport, immune and metabolic signaling, and host-microbiome interactions, with downstream implications for drug disposition and biomarker interpretation. This complexity is further compounded by rapid clearance and limited systemic availability, although partially offset by the functional relevance of bioactive metabolites. Consistent with this pleiotropic model, clinical signals of curcumin activity tend to emerge in conditions characterized by multifactorial dysregulation, including metabolic, neurocognitive, and musculoskeletal disorders, as well as microbiome-associated alterations. Notably, human studies and meta-analyses frequently report divergent outcomes, with some trials demonstrating benefit and others showing substantial between-study heterogeneity. To reconcile these discrepancies, we advocate a High Input, Rational Integration paradigm that unifies experimental, preclinical, and clinical evidence obtained through logically rigorous and strictly consistent procedures applied across comprehensive, convergent, and reproducible datasets. Within the hierarchical organization of curcumin\u2019s pharmacology, this approach enables the synthesis of mechanistic diversity within pharmacokinetic and physiological constraints and, more broadly, provides a coherent framework for interpreting pleiotropic bioactives in human studies.<\/jats:p>","DOI":"10.3390\/ijms27052212","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T14:51:29Z","timestamp":1772117489000},"page":"2212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Curcumin Between Pleiotropic Potential and Translational Constraints"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2750-6226","authenticated-orcid":false,"given":"Alessandro","family":"Magini","sequence":"first","affiliation":[{"name":"Department of Agricultural, Food, and Environmental Sciences, University of Perugia, 06121 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Datti","sequence":"additional","affiliation":[{"name":"Department of Agricultural, Food, and Environmental Sciences, University of Perugia, 06121 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/978-0-387-46401-5_3","article-title":"Antioxidant and anti-inflammatory properties of curcumin","volume":"Volume 595","author":"Aggarwal","year":"2007","journal-title":"The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.biocel.2008.06.010","article-title":"Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases","volume":"41","author":"Aggarwal","year":"2009","journal-title":"Int. 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