Novel Therapeutic Strategies Targeting EZH2 and NLRP3 in Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) is one of the most common and aggressive human malignancies worldwide, characterized by high rates of proliferation, invasiveness, and metastasis. Despite the use of surgical resection, chemotherapy, and radiotherapy as standard treatments, OSCC still shows poor prognosis and low survival rates, highlighting the urgent need for novel therapeutic strategies. Among the molecular mechanisms implicated in OSCC progression, recent evidence has identified a key role for both the NLRP3 inflammasome and the epigenetic regulator EZH2. This study aimed to evaluate the effects of two selective inhibitors: BAY 11-7082, targeting the NLRP3 inflammasome, and GSK343, an EZH2 inhibitor through both in vitro and in vivo approaches. BAY 11-7082 (5, 10, and 30 μM) significantly reduced OSCC cell viability and decreased the expression of NLRP3, ASC, caspase-1, IL-1β, and IL-18. It also enhanced pro-apoptotic markers such as Bax, Bad, and p53, while reducing anti-apoptotic Bcl-2. In xenograft mouse models, BAY 11-7082 (2.5 and 5 mg/kg) decreased tumor mass and suppressed inflammasome activation. Similarly, GSK343 (1, 10, and 25 μM) reduced OSCC cell viability and migration in vitro by inhibiting EZH2 and modulating NFκB/IκBα signaling, as well as angiogenesis-related markers (eNOS, VEGF, TGFβ). In orthotopic mouse models, GSK343 (5 and 10 mg/kg) restored tissue architecture and reduced tumor growth via EZH2 and Wnt/β-catenin pathway modulation, also decreasing CD31 and CD34 expression. These findings support the potential therapeutic role of BAY 11-7082 and GSK343 in OSCC by targeting key inflammatory and epigenetic pathways involved in tumor progression.