Jingkun Chen,1 Xiaohui Zheng,2 Xiaobing Wang,3 Ching-Feng Weng2,4 

1Department of Stomatology, Zhongshan Hospital Affiliated with Xiamen University, Xiamen, 361004, People’s Republic of China; 2Department of Physiology, School of Basic Medical Sciences, Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen, 361023, People’s Republic of China; 3Department of Pharmacy, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, 361004, People’s Republic of China; 4Leadtek Biomedical, Inc, New Taipei City, 235603, Taiwan

Correspondence: Xiaohui Zheng, Email 201500010365@xmmc.edu.cn Ching-Feng Weng, Email cfwengcf@gmail.com

Background: Oral tongue squamous cell carcinoma (OTSCC), the most prevalent oral malignancy, lacks effective treatments.
Objective: Evaluate Evodia lepta (E. lepta) as a potential OTSCC therapeutic.
Methods: Cell viability (CCK-8) and protein expression (Western blot) were assessed in OTSCC (CAL27, TCA8113) and 3T3 cells after 24h treatment with E. lepta or cisplatin.
Results: Cisplatin significantly reduced the viability in all cells (IC50: 3T3 = 9.5 μM; CAL27/TCA8113 = 3.5 μM). E. lepta selectively targeted OTSCC cells (IC50: CAL27 = 80 μg/mL; TCA8113 = 60 μg/mL) with no 3T3 toxicity. Protein expression analysis revealed that E. lepta downregulated GPX4, ADRM1, MMP14, PD-L1, and HSPA5 in both CAL27 and 3T3 cells. Interestingly, the expression of p17 exhibited divergent regulation between cell types. In contrast, cisplatin treatment upregulated GPX4 and downregulated MMP14, PD-L1, and HSPA5 in CAL27 cells, with p17 regulation opposing that observed with E. lepta.
Conclusion: E. lepta selectively induces ferroptosis through GPX4 and HSPA5 downregulation, demonstrating multi-target effects including proteostasis disruption (ADRM1), metastasis inhibition (MMP14), and immune evasion suppression (PD-L1). Its GPX4 suppression contrasts with cisplatin’s upregulation, suggesting utility in cisplatin-resistant OTSCC. PD-L1 reduction implies immunotherapeutic potential, meriting further study.

Keywords: Evodia lepta, cisplatin, tongue cancer, cytotoxicity, mechanism