Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy with limited effective treatment options. This study aimed to explore the therapeutic potential of novel pyrazole N-aryl sulfonate derivatives (compounds 4b, 4d, and 5f) as selective cyclooxygenase-2 (COX-2; prostaglandin-endoperoxide synthase 2, PTGS2) inhibitors in OSCC. Using CCK-8 and Transwell assays, we evaluated the anti-proliferative and anti-migratory effects of these compounds on CAL-27 and SAS cell lines, while apoptosis was assessed by Hoechst 33342 staining and flow cytometry. Molecular mechanisms were investigated through RT-qPCR, Western blot, and ELISA, focusing on COX-2, MMP2, MMP9, BCL2, BAX, and the JAK/STAT3 pathway. The results demonstrated that compounds 4b, 4d, and 5f significantly inhibited cell proliferation and migration, induced apoptosis, and downregulated the expression of COX-2 and its downstream targets. Notably, these compounds exhibited lower cytotoxicity in VERO cells, indicating favorable biological safety. In conclusion, our findings suggest that pyrazole N-aryl sulfonate derivatives effectively suppress OSCC cell growth and migration by targeting COX-2 and the JAK/STAT3 pathway, highlighting their promise as potential targeted therapeutics for OSCC.

Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with a poor prognosis. Sestrin2 (Sesn2), a stress-inducible protein, has been implicated in various cancers, but its precise role and mechanism in OSCC remain unclear. This study investigated the molecular mechanisms of Sesn2 in OSCC. Sesn2 expression was analyzed using data from TCGA and immunohistochemical results from the HPA. Functional assays, including CCK-8, flow cytometry for cell cycle, wound healing, and Transwell assays, were performed following Sesn2 knockdown with siRNA in OSCC cell lines (CAL-27 and SAS). Underlying mechanisms were investigated by Western blotting and ELISA for MMP-2 and MMP-9 levels. Sesn2 was significantly upregulated in OSCC tissues compared to normal controls. Its knockdown markedly suppressed cell proliferation, induced G1 phase cell cycle arrest, and impaired migratory and invasive capabilities. This reduction in invasion was further confirmed by decreased levels of MMP-2 and MMP-9 upon Sesn2 knockdown. Furthermore, Sesn2 silencing induced apoptosis via Caspase-3 activation with divergent BAX/BCL-2 modulation; SAS cells exhibited elevated BAX and reduced BCL-2, whereas these proteins remained unchanged in CAL-27 cells. Mechanistically, we found that Sesn2 depletion downregulated the PI3K/AKT/mTOR pathway and reduced the phosphorylation of AKT and p38 MAPK. Our findings demonstrate that Sesn2 functions as an oncogene in OSCC, promoting tumor progression by modulating the PI3K/AKT/mTOR and MAPK signaling pathways, suggesting its potential as a therapeutic target for OSCC.