Salivary thioredoxin-1 as a non-invasive redox biomarker in oral diseases

Table 1 Molecular actions of thioredoxin-1 and their relevance in oral diseases

Molecular function of thioredoxin-1	Associated pathway or target	Biological effect	Relevance in oral diseases
Antioxidant activity	Reactive oxygen species scavenging pathways	Reduction of oxidative stress and maintenance of redox balance	Protection against periodontal tissue destruction and oxidative cellular injury
Redox regulation	Nuclear factor kappa B and activator protein-1 signaling pathways	Regulation of inflammatory cytokine production and inflammatory signaling	Contribution to chronic inflammation in periodontal diseases
Inhibition of apoptosis	Apoptosis signal-regulating kinase 1 pathway	Prevention of programmed cell death and promotion of cell survival	Survival of dysplastic and malignant cells in oral lesions
Support of DNA synthesis and repair	Ribonucleotide reductase pathway	Promotion of cellular proliferation and genomic maintenance	Facilitation of progression in oral potentially malignant disorders and oral squamous cell carcinoma
Promotion of angiogenesis	Redox-sensitive angiogenic signaling pathways	Formation of new blood vessels and enhancement of tumor microenvironment	Tumor progression and metastatic potential in oral squamous cell carcinoma
Extracellular signaling activity	Cytokine-like immunomodulatory pathways	Regulation of immune and inflammatory responses	Basis for its detectability and utility as a salivary biomarker

Table 2 Review of studies evaluating the role of theoredoxin-1 in oral diseases

Ref.	Study design & cohort/model	Biomarker & analyzed biofluid matrix	Key clinical findings/diagnostic & therapeutic metrics	Methodological weaknesses & risks of bias	Biological resolution of discrepancies (high vs low levels)
Lorente et al[46], 2026	Prospective observational clinical study (n = 144)	Salivary Trx-1 measured in unstimulated whole cell-free supernatant	Salivary Trx-1 levels were significantly lower in patients with periodontitis than in healthy controls (P < 0.001). Trx-1 showed a moderate negative correlation with tissue destruction severity (ρ = –0.47, P < 0.001). A diagnostic cut-off of ≤ 41.55 ng/mL achieved an AUC of 75%, with 83% sensitivity and 63% specificity	Participants were not adequately controlled or stratified for chronic systemic inflammatory comorbidities, introducing potential selection bias. In addition, no a priori sample size or statistical power calculation was reported	Chronic periodontal inflammation produces sustained oxidative stress and neutrophil activation, progressively exhausting the local antioxidant reserve. Consequently, extracellular salivary Trx-1 decreases because antioxidant consumption exceeds its production and secretion
Amirchaghmaghi et al[52], 2020	Comparative cross-sectional clinical study (n = 88)	Salivary Trx-1 measured in unstimulated whole cell-free supernatant	Salivary Trx-1 levels followed the trend healthy > OSCC > OLP, although the overall difference was not statistically significant (P = 0.135). Keratotic OLP demonstrated significantly higher Trx-1 levels (P = 0.003), while patients with OSCC aged > 65 years showed markedly elevated concentrations (P = 0.001)	A considerable age imbalance between the study groups introduced potential age-related redox confounding. Disease subgroup analyses were also limited by relatively small sample sizes	Trx-1 demonstrates a biphasic biological response. During early inflammatory and premalignant stages, Trx-1 is upregulated to protect against oxidative DNA damage. As malignancy progresses, tumor cells increasingly retain intracellular Trx-1 to support proliferation and survival, reducing its extracellular release into saliva
Iwasawa et al[53], 2011	Retrospective molecular validation and immunohistochemical tissue study (n = 50).	TrxR1 gene and protein expression evaluated in primary OSCC tissue and matched healthy surgical margins	TXNRD1 expression was increased by approximately 5.10-fold in OSCC tissues compared with healthy controls (P < 0.01). High cytoplasmic TrxR1 protein expression was significantly associated with lymph node metastasis (P = 0.027) and advanced clinical stage III/IV disease (P = 0.007)	The investigation evaluated only intracellular tissue expression and therefore could not determine trans-epithelial transfer into saliva. Semi-quantitative immunohistochemical scoring also introduced potential observer bias	The findings support intracellular sequestration of the thioredoxin system within malignant cells. Increased TrxR1 activity enables tumor survival under oxidative stress while limiting extracellular diffusion of Trx-1 into saliva, thereby explaining reduced salivary concentrations despite high tissue expression
Wu et al[34], 2023	Experimental pre-clinical in vivo diabetic mouse model combined with in vitro periodontal ligament stem cell experiments	Trx-1 expression evaluated in periodontal tissues and cultured periodontal ligament stem cells	Knockdown of Trx-1 inhibited osteogenic differentiation through disruption of the Wnt/β-catenin signaling pathway. Administration of recombinant human Trx-1 reduced reactive oxygen species, restored Wnt/β-catenin signaling, and significantly rescued alveolar bone loss in diabetic mice	Animal models cannot fully replicate the complexity of the human oral environment, including salivary matrix effects, systemic influences, lifestyle factors, and enzymatic degradation	These experimental findings demonstrate that excessive oxidative stress directly suppresses endogenous Trx-1 expression. Restoration of Trx-1 activity reverses oxidative injury, supports osteogenesis, and validates antioxidant depletion as a major mechanism underlying severe periodontal disease

Trx-1: Thioredoxin-1; TrxR1: Thioredoxin reductase-1; OSCC: Oral squamous cell carcinoma; OLP: Oral lichen planus; TXNRD1: Thioredoxin reductase 1 gene; Wnt: Wingless/integrated signaling pathway; β-catenin: Beta-catenin; AUC: Area under the curve.