Curcumin and Its Protein Targets: Literature Review and Systems Biology Analysis

The pleiotropic pharmacological action of curcumin, a compound derived from Curcuma longa L. rhizome, may result from its direct interaction with key cellular proteins or modulation of their gene expression. Despite the focus on elucidating curcumin's mechanisms of action, there is no comprehensive analysis of protein targets of curcumin associated with human diseases over the past 5 years. We collected and analyzed 166 unique protein targets of curcumin from 96 relevant articles published between 1 January, 2021 and 1 July, 2025. The source of evidence for each target was categorized as bioinformatics hypothesis, in silico prediction, or in vitro verification. Only seven targets were experimentally verified, highlighting a substantial gap between in silico predictions and experimental validation. The analysis identified the most frequently reported targets, such as EGFR, STAT3, AKT1, TNF, and CASP3. Several of these, particularly EGFR, STAT3, and AKT1, also function as hub proteins and are associated with up to 18 different diseases. A large group of targets (94 proteins) was found to be associated with proliferative diseases, primarily colorectal, breast, and non-small cell lung cancers. Additionally, a distinct subset of 60 targets was shown to be involved in molecular ageing. Functional enrichment analysis indicated that the entire set of targets are highly interconnected and overrepresented in cell proliferation (81 targets), communication (66), and migration (40). Furthermore, at least 14 targets (e.g., CDK2, EGFR, and GSK3B) were found to be common to both curcumin and its derivatives. That is crucial for the design of curcumin derivatives with improved pharmacokinetics. The in silico and in vitro studies suggest that curcumin can act as a drug prototype targeting protein-protein interaction interfaces. This review broadens the understanding of curcumin pharmacological action and provides a foundation for future experimental studies on its protein targets verification.