HPGD induces ferroptosis and autophagy to suppress esophageal squamous cell carcinoma through the LXA4–ERK1/2–U2AF2–TFRC axis

This study provides the first systematic analysis of HPGD expression in esophageal squamous cell carcinoma (ESCC) and its clinical correlation with poor differentiation. The research reveals HPGD's dual mechanisms of inducing ferroptosis and autophagy through TFRC regulation, offering novel therapeutic targets for ESCC.

 

Literature Overview
The article "HPGD induces ferroptosis and autophagy to suppress esophageal squamous cell carcinoma through the LXA4–ERK1/2–U2AF2–TFRC axis" published in Molecular Cancer investigates the expression patterns of 15-hydroxyprostaglandin dehydrogenase (HPGD) in ESCC and its association with tumor differentiation and patient prognosis. The study elucidates the molecular mechanism where HPGD regulates RNA-binding protein U2AF2 binding to the transferrin receptor (TFRC) promoter through LXA4-dependent ERK1/2 signaling, thereby inducing ferroptosis and autophagy.

Background Knowledge
Esophageal squamous cell carcinoma (ESCC) is a high-incidence cancer globally, particularly with high morbidity and low survival rates in China. As the primary metabolic enzyme of lipoxin A4 (LXA4), HPGD has demonstrated tumor-suppressive roles in gastric cancer and colorectal cancer. However, its functional mechanisms in ESCC remain uncharacterized. This study represents the first systematic exploration of HPGD's clinical significance in ESCC, revealing its novel tumor-inhibitory mechanisms through multi-omics approaches. TFRC, a critical receptor for iron uptake, plays key roles in ferroptosis, but its upstream regulatory signals are incompletely understood. The research further identifies HPGD's promotion of U2AF2 binding to the TFRC promoter via LXA4–ERK1/2 pathways, leading to TFRC upregulation, ferroptosis induction, and autophagy activation. Additionally, the team validated HPGD's anti-tumor effects through in vivo xenograft models, providing theoretical foundations for future targeted therapies.

 

 

Research Methods and Experiments
The research team conducted transcriptome sequencing on paired tumor and adjacent normal tissues to identify HPGD as a significantly downregulated gene. They subsequently validated its expression and prognostic significance in two independent ESCC patient cohorts. Functional impacts were assessed through HPGD overexpression in ESCC cell lines, analyzing cell proliferation, apoptosis, migration, and invasion. Comprehensive mechanisms of HPGD-regulated TFRC expression and ferroptosis/autophagy induction were dissected using transcriptome sequencing, lipid peroxidation assays, ROS level analysis, ChIP, FISH, flow cytometry, and mouse xenograft models.

Key Conclusions and Perspectives

• HPGD is significantly downregulated in ESCC tissues, showing negative correlation with tumor differentiation and patient prognosis.
• HPGD overexpression markedly suppresses ESCC cell proliferation, invasion, and migration while promoting apoptosis.
• HPGD induces TFRC upregulation through LXA4–ERK1/2 signaling, enhancing iron accumulation and ferroptosis.
• TFRC upregulation activates the AMPK–mTOR pathway, promoting autophagy.
• TFRC knockdown or ROS inhibition reverses HPGD-induced ferroptosis and autophagy, restoring malignant phenotypes.
• ChIP and FISH experiments confirm U2AF2 binding to the TFRC promoter region, which is regulated by HPGD.
• HPGD significantly suppresses tumor growth in mouse xenograft models, validating its in vivo anti-tumor function.

Research Significance and Prospects
This study pioneers the understanding of HPGD's tumor-suppressive role and molecular mechanisms in ESCC, establishing its value as a potential prognostic biomarker and therapeutic target. Future research should explore HPGD regulatory mechanisms, assess its feasibility as a drug target, and evaluate therapeutic strategies targeting TFRC or U2AF2. Additionally, these findings provide novel insights into non-canonical functions of RNA-binding proteins in transcriptional regulation.

 

 

Conclusion
This work systematically investigated HPGD's functions in esophageal squamous cell carcinoma (ESCC), demonstrating its significant clinical correlation with tumor differentiation and patient prognosis. HPGD promotes LXA4 degradation, inhibits ERK1/2 signaling, enhances U2AF2 binding to the TFRC promoter, and upregulates TFRC expression leading to iron accumulation and ferroptosis. ROS accumulation during ferroptosis activates the AMPK–mTOR pathway, inducing autophagy. The study validated HPGD's anti-tumor effects through in vivo xenograft models and uncovered U2AF2's novel transcriptional regulatory role. This mechanism provides new molecular targets and theoretical foundations for ESCC therapy, while opening avenues for non-canonical RNA-binding protein research in cancer.

 

Tianyun Ma, Xiamei Guo, Jueying Zhao, Qilong Wang, and Chao Luo. HPGD induces ferroptosis and autophagy to suppress esophageal squamous cell carcinoma through the LXA4–ERK1/2–U2AF2–TFRC axis. Molecular Cancer.