Evaluation of the Nrf2–Keap1 and Sestrin-2 Pathways in the Serum of Patients with Hidradenitis Suppurativa

Abstract

Background and Objectives: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterised by recurrent nodules, abscesses, sinus tract formation, and tissue remodelling. Increasing evidence suggests that oxidative stress contributes to HS pathogenesis; however, the role of the Nrf2–Keap1–Sestrin-2 axis and its interaction with matrix remodelling pathways remains poorly understood. This study aimed to evaluate serum levels of Nrf2, Keap1, Sestrin-2, asprosin, MMP-1, and TIMP-1 in patients with HS and to investigate their potential roles in disease pathophysiology. Materials and Methods: A total of 26 patients with hidradenitis suppurativa and 20 healthy volunteers were enrolled in the study. Serum biomarkers were measured in patients with HS and healthy controls. In addition to conventional statistical analyses, multivariate analyses, including PCA, PLS-DA, VIP scoring, correlation mapping, ROC analysis, heatmap visualisation, and biplot assessment, were performed to characterise biomarker interactions and discriminatory performance. Results: HS patients exhibited significantly increased serum asprosin, Keap1, and MMP-1 levels, whereas Nrf2, Sestrin-2, and TIMP-1 levels were significantly reduced compared with controls. Multivariate analyses demonstrated clear separation between patient and control groups within the cohort, indicating a distinct biochemical signature associated with HS. VIP analysis identified Nrf2, Sestrin-2, and TIMP-1 as the most influential variables contributing to group discrimination. Within the HS group, none of the pairwise biomarker correlations remained statistically significant after Benjamini–Hochberg false discovery rate (FDR) correction. ROC analysis showed diagnostic performance for Nrf2 and Sestrin-2. Conclusions: These findings suggest that alterations in serum markers related to the Nrf2–Keap1–Sestrin-2 axis and the MMP-1/TIMP-1 balance are associated with oxidative stress, inflammation, and tissue remodelling in HS. Nrf2 and Sestrin-2 may represent candidate biomarkers; however, given the modest sample size and single-centre design, their discriminatory performance should be considered exploratory and requires confirmation in larger independent cohorts.