Oleuropein regulates ubiquitination-mediated Mcl-1 turnover and exhibits antitumor activity.

Oral squamous cell carcinoma (OSCC) represents the most common type of malignant oral tumor, with a high prevalence globally. Despite continual advancements in OSCC treatment, the 5-year survival rate remains around 50%, highlighting an urgent need for the development of new and effective therapeutic strategies. Here, we focused on myeloid leukemia 1 (Mcl-1), a well-known oncogenic driver in various human cancers, and systematically explored the therapeutic potential of oleuropein (Ole) through in vitro and in vivo analyses. Our findings demonstrated that Ole suppressed OSCC cell viability dose-dependently. Mechanistically, Ole facilitated β-TRCP-mediated ubiquitination of Mcl-1 by inhibiting the Akt-GSK3β-Mcl-1 pathway and enhancing the collaboration between β-TRCP and Mcl-1, ultimately leading to Mcl-1 degradation. Furthermore, the knockdown of β-TRCP mitigated the inhibitory effects of Ole on OSCC cells. In agreement with our cell-based experiments, animal studies showed that Ole treatment significantly delayed tumor growth without causing toxicity to vital organs. Additionally, whether used alone or combined with radiation, Ole effectively overcame radioresistance in OSCC cells. Our results suggest that Ole is a promising anti-tumor agent capable of treating OSCC by targeting Mcl-1.