Molecular Cancer | HPGD suppresses esophageal squamous cell carcinoma by inducing ferroptosis and autophagy through the LXA4-ERK1/2-U2AF2-TFRC axis

This study is the first systematic investigation to reveal HPGD expression in esophageal squamous cell carcinoma (ESCC) and its correlation with patient prognosis. It demonstrates that HPGD suppresses tumor progression by inducing ferroptosis and autophagy through the LXA4-ERK1/2-U2AF2-TFRC signaling axis, providing potential therapeutic targets for ESCC treatment.

 

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 reveals that HPGD expression is significantly downregulated in ESCC tissues and positively correlates with tumor differentiation and patient prognosis. Through multiple in vitro and in vivo experiments, the study identifies that HPGD promotes LXA4 degradation, inhibits the ERK1/2 signaling pathway, enhances RNA-binding protein U2AF2 binding to the TFRC promoter region, upregulates TFRC expression, and ultimately induces ferroptosis and autophagy to suppress ESCC progression.

Background Knowledge
Esophageal squamous cell carcinoma (ESCC) is a globally prevalent malignancy with high mortality rates closely linked to late-stage diagnosis and suboptimal therapeutic outcomes. While integrative bioinformatics approaches have advanced cancer research in recent years, the molecular mechanisms underlying ESCC remain incompletely understood. 15-Hydroxyprostaglandin dehydrogenase (HPGD), a key metabolic enzyme for prostaglandins and LXA4, exhibits tumor-suppressive properties in multiple cancers, yet its role in ESCC remains uncharacterized. This study systematically analyzes HPGD expression, function, and molecular mechanisms in ESCC, establishing its potential as a therapeutic target.

 

 

Research Methods and Experiments
The research team first performed transcriptome sequencing on paired tumor and adjacent normal tissues from 5 ESCC patients to identify differentially expressed genes. Subsequently, HPGD expression and its prognostic relevance were validated in two independent large-scale ESCC cohorts. In vitro, HPGD overexpression in KYSE30 and KYSE150 cells was conducted using proliferation, migration, invasion, and apoptosis assays to evaluate functional impacts. RNA sequencing and bioinformatics analyses further explored gene expression changes following HPGD overexpression, particularly those related to ferroptosis and autophagy. Mechanistically, lipid peroxidation assays, ROS measurement, dual-fluorescence reporter assays, protein microarrays, streptavidin pull-down, and ChIP experiments elucidated how HPGD induces ferroptosis and autophagy through the LXA4-ERK1/2-U2AF2-TFRC axis.

Key Conclusions and Perspectives

• HPGD expression is significantly downregulated in ESCC tissues and correlates with poor tumor differentiation and unfavorable patient outcomes.
• HPGD overexpression markedly suppresses ESCC cell proliferation, migration, and invasion while promoting apoptosis.
• HPGD promotes LXA4 degradation, inhibits ERK1/2 signaling, enhances U2AF2 binding to the TFRC promoter region, and upregulates TFRC expression.
• TFRC overexpression induces ferroptosis and activates autophagy via the AMPK/mTOR pathway, creating a positive feedback loop.
• In vivo experiments confirm that HPGD overexpression suppresses tumor growth while increasing ROS and iron ion levels and reducing GPX4 activity.
• Targeting TFRC or inhibiting ferroptosis reverses HPGD-induced autophagy activation and tumor suppression.

Research Significance and Prospects
This study systematically characterizes the tumor-suppressive role of HPGD in ESCC and establishes its molecular mechanisms, providing theoretical foundations for targeting HPGD and its downstream signaling axis. Future research may focus on developing small-molecule drugs or gene therapies targeting this pathway for precision medicine applications in ESCC. Additionally, the novel transcriptional regulatory function of U2AF2 may expand its recognized roles in RNA-binding protein research.

 

 

Conclusion
This study systematically uncovers the tumor-suppressive mechanism of 15-hydroxyprostaglandin dehydrogenase (HPGD) in esophageal squamous cell carcinoma (ESCC). It demonstrates that HPGD is significantly downregulated in ESCC and associated with poor patient prognosis. Through comprehensive in vitro and in vivo experiments, the researchers confirm that HPGD suppresses ESCC progression by promoting LXA4 degradation, inhibiting ERK1/2 signaling, enhancing U2AF2 binding to the TFRC promoter region, and upregulating TFRC expression. This sequential activation of ferroptosis and autophagy through a positive feedback mechanism provides novel insights for HPGD's tumor-suppressive functions in cancers and opens new avenues for targeted ESCC therapies. Future investigations may explore small-molecule modulators or gene therapy strategies targeting this signaling axis to improve clinical outcomes.

 

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.