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

Area of Science:

• Oncology
• Cell Death Mechanisms
• Molecular Biology

Background:

• Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, with survival rates below 20%.
• Ferroptosis, an iron-dependent cell death, is a potential therapeutic target, but its regulation in ESCC is unclear.
• Tripartite motif-containing 31 (TRIM31), an E3 ubiquitin ligase, role in ESCC and ferroptosis was investigated.

Purpose of the Study:

• To investigate the role of TRIM31 in ESCC progression.
• To elucidate the mechanism by which TRIM31 affects ferroptosis in ESCC.
• To evaluate TRIM31 as a therapeutic target for ESCC.

Main Methods:

• Analysis of TRIM31 expression in ESCC tissues and correlation with clinical parameters.
• Functional assays (cell proliferation, colony formation, migration) following TRIM31 knockdown.
• In vivo xenograft studies to assess tumor growth and proliferation.
• Co-immunoprecipitation and Western blotting to study TRIM31-VDAC1 interaction and ubiquitination.
• Assessment of ferroptosis markers (lipid ROS, Fe2+ levels, mitochondrial morphology).
• Identification of TRIM31 transcriptional activator using promoter assays.

Main Results:

• TRIM31 was significantly upregulated in ESCC tissues and correlated with advanced TNM stage, metastasis, and poor survival.
• TRIM31 knockdown suppressed ESCC cell proliferation, migration, and xenograft tumor growth.
• TRIM31 directly interacted with VDAC1, promoting its ubiquitination and degradation, thereby inhibiting ferroptosis.
• TRIM31 overexpression attenuated RSL3-induced ferroptosis.
• Hepatocyte nuclear factor 4 alpha was identified as a transcriptional activator of TRIM31.
• TRIM31 knockdown synergized with imidazole ketone erastin to reduce tumor growth by 90% with minimal toxicity.

Conclusions:

• TRIM31 promotes ESCC progression by degrading VDAC1 and suppressing ferroptosis.
• Targeting TRIM31 enhances ferroptosis-based therapies.
• TRIM31 represents a novel, clinically actionable therapeutic target for ESCC.