IL-18 and NFE2L2/NRF2 in Adult ADHD: An Inflammation-Redox Framework for Salivary Biomarker Research

Int J Mol Sci. 2026 Oct 30;27(21):9732. doi: 10.3390/ijms27219732.

ABSTRACT

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder, and increasing evidence suggests that inflammatory and oxidative processes may contribute to its biological complexity. Despite these observations, no molecular biomarker has yet been established for clinical diagnosis. In this narrative review, we examine interleukin-18 (IL-18) and the NFE2L2/NRF2 antioxidant pathway as two potentially complementary components of the inflammation-redox landscape in adult ADHD, with particular attention to their possible assessment in saliva. For this purpose, we conducted a focused search of PubMed/MEDLINE, Scopus, and Web of Science, bringing together evidence from human ADHD studies, mechanistic and experimental research, and studies investigating the feasibility of salivary biomarkers. IL-18 is closely associated with inflammasome-mediated inflammatory signaling, whereas NFE2L2 encodes NRF2, a major regulator of antioxidant and cytoprotective responses. The evidence for these two targets in adult ADHD is not equally developed. Direct human data on IL-18 remain limited, while more recent studies have identified alterations in NRF2-related antioxidant defenses in adults with ADHD. Both IL-18 and NRF2 can be measured in human saliva, although the available evidence comes from clinical populations other than ADHD. Their detection in saliva therefore demonstrates analytical feasibility but does not establish their validity as ADHD biomarkers. At present, neither marker has been validated in the saliva of adults with ADHD. Studying them together may nevertheless provide a useful way to explore the relationship between inflammatory activity and antioxidant regulation. Future studies will require standardized saliva collection, careful assessment of oral health, and characterization of systemic inflammatory and metabolic conditions, medication use, and smoking. Initial studies should also include paired saliva and blood samples to determine how salivary measurements relate to circulating levels and whether they capture biologically meaningful variation in adult ADHD.

PMID:43027979 | DOI:10.3390/ijms27219732