Targeting TRIM31 to Boost Ferroptosis: A Promising Approach for Esophageal Cancer Therapy

Aims: Esophageal squamous cell carcinoma (ESCC) is among the most lethal malignancies worldwide, with a five-year survival rate below 20%. Ferroptosis—a regulated form of cell death driven by iron-dependent lipid peroxidation—has emerged as a promising therapeutic strategy, yet its regulation in ESCC remains poorly understood. We investigated the role of tripartite motif-containing 31 (TRIM31), an E3 ubiquitin ligase, in ESCC progression and ferroptosis. Results: TRIM31 expression was significantly elevated in ESCC tissues compared with normal esophageal tissues (The Cancer Genome Atlas and Genotype-Tissue Expression datasets; p < 0.001) and correlated with advanced Tumor, Node, and Metastasis (TNM) stage ( p = 0.004), lymph node metastasis ( p = 0.024), and poor overall survival ( p = 0.0027). Functional assays revealed that TRIM31 knockdown reduced ESCC cell proliferation, impaired colony formation, and suppressed migration ( p < 0.01). In vivo , TRIM31 silencing decreased xenograft tumor volume by over 70% and Ki-67 expression by 73%. Mechanistically, TRIM31 directly interacted with VDAC1 via its coiled-coil domain, promoting VDAC1 ubiquitination and proteasomal degradation. This interaction inhibited ferroptosis, as evidenced by increased lipid reactive oxygen species, elevated intracellular Fe 2+ levels, and mitochondrial damage upon TRIM31 knockdown. Conversely, TRIM31 overexpression attenuated ferroptosis induced by RSL3. We further identified hepatocyte nuclear factor 4 alpha as a transcriptional activator of TRIM31, binding to its promoter region. Importantly, TRIM31 knockdown synergized with the ferroptosis inducer imidazole ketone erastin, achieving a 90% reduction in tumor growth without significant toxicity. Conclusion: TRIM31 promotes ESCC progression by degrading VDAC1 and suppressing ferroptosis. Targeting TRIM31 enhances ferroptosis-based therapy and represents a novel, clinically actionable strategy for ESCC treatment. Antioxid. Redox Signal. 00, 000–000.