The biological clock gene PER2 promotes PANoptosis in oral squamous cell carcinoma by facilitating the formation of the Caspase-8/RIPK3/ASC complex

Current research indicates that the circadian clock gene PER2 plays a significant role in preventing tumor. However, its specific mechanism of action in oral squamous cell carcinoma (OSCC) remains unclear. While it is known that PANoptosis is critical for tumor suppression, whether PER2 exerts its anti-cancer effects by regulating this process has not been determined. Through bioinformatics analysis, our analysis revealed that PANoptosis-related genes (MAP3K7, CASP8) significantly correlate with the prognosis of OSCC patients. In OSCC cell lines (NOK, CAL27, SCC25, SCC15) and clinical samples, PER2 expression demonstrated an extremely positive correlation with CASP8 and a negative association with MAP3K7. The overexpression of PER2 significantly suppressed OSCC cell proliferation, promoted apoptosis, and increased both lactate dehydrogenase release and the expression of PANoptosis markers (cleaved caspase-3, N-GSDME, p-MLKL). In agreement with the in vitro findings, tumor xenograft experiments in vivo demonstrated that elevated PER2 expression inhibits tumor growth and upregulates the expression of PANoptosis markers. Mechanistically, PER2 binds to and stabilizes Caspase-8 protein, facilitating formation of the Caspase-8/RIPK3/ASC complex in OSCC cells. Notably, treatment with the Caspase-8 inhibitor Z-IETD-FMK markedly reversed PANoptosis in OSCC cells. This study provides the first evidence that PER2 overexpression suppresses OSCC proliferation by regulating the Caspase-8/RIPK3/ASC complex-mediated PANoptosis, offering a promising therapeutic strategy for OSCC.