Sirtuin 4 is downregulated in oral carcinogenesis

Metabolic reprogramming is a defining characteristic of cancer. Sirtuin 4 (SIRT4) has been demonstrated to modulate tumor metabolism and influence proliferation, migration, and stress responses across various cancer types. However, its roles in oral carcinogenesis remain uncertain. This study aims to investigate SIRT4 expression in oral squamous cell carcinoma (OSCC) and oral epithelial dysplasia (OED) and its correlation with clinical-pathological characteristics. Ninety patients were evenly divided into three groups: benign, non-dysplastic keratosis, OED, and OSCC. SIRT4 expression was analyzed immunohistochemically, with assessment based on staining intensity and percentage of positively stained squamous epithelial cells. The correlation between clinical-pathological features of OSCC and SIRT4 level was evaluated. We found that SIRT4 expression was significantly reduced in OED and OSCC, compared with benign hyperkeratosis. Conversely, no difference in SIRT4 was detected between OED and OSCC. SIRT4 was predominantly localized to the spinous cell layers in OED and benign keratosis. In OSCC, SIRT4 expression exhibited mild staining intensity and was primarily confined to the central squamous cells within the invasive tumor nests. Additionally, SIRT4 expression was not associated with the clinical-pathologic variables of OSCC. SIRT4 downregulation is observed in the initial stages of oral dysplastic alterations and persists throughout the progression of OSCC. SIRT4 may act as a tumor suppressor and serve as an early candidate biomarker of oral malignant changes. Its loss may signify a metabolic shift crucial to the development of oral cancer. Future studies should investigate whether SIRT4 could represent a potential therapeutic target in patients with OED and OSCC.