Piperine targets SOAT1 to inhibit the progression of esophageal squamous cell carcinoma via ferroptosis

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a major contributor to cancer-associated mortality worldwide. Therefore, there is an urgent need to identify novel therapeutic targets and treatment modalities for this disease. Piperine, a natural alkaloid, has been shown to possess notable anticancer properties. However, the anticancer efficacy of piperine in ESCC and its underlying molecular mechanisms remain unclear. PURPOSE: This study aimed to investigate the anticancer effect and molecular mechanism of piperine in ESCC. METHODS: To evaluate the anticancer potential of piperine against ESCC, a series of experiments was conducted. These included key gene knockdown, CCK-8 assays, colony formation tests, molecular docking studies, bioinformatics analyses, Western blotting, and real-time PCR arrays. RESULTS: Piperine inhibited cell proliferation, migration, and invasion. Importantly, piperine was identified as a potential Sterol O-acyltransferase 1 (SOAT1) inhibitor. Interestingly, piperine targets SOAT1 to enhance ferroptosis and inhibit cell viability. Furthermore, piperine targets SOAT1 to synergistically enhance the anticancer effects of cisplatin in ESCC. Further data analysis showed that inhibiting SOAT1 increased KLF4-induced ALOX12B expression by decreasing the PI3K-AKT pathway. Finally, in vivo studies demonstrated that the SOAT1 inhibitor piperine hindered tumor growth in mice without altering body weight. CONCLUSION: This study is the first to demonstrate that piperine targets SOAT1 to enhance ferroptosis by inhibiting the PI3K-AKT axis and upregulating the expression of KLF4/ALOX12B. This study strongly emphasizes the potential of piperine as a promising clinical therapeutic candidate for ESCC.