HILPDA, Regulated by WTAP in an m6A-Dependent Manner, Enhances Osteosarcoma Development by Inhibiting Ferroptosis and...

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Osteosarcoma (OS) is the most common primary bone cancer.
• Hypoxia-inducible lipid droplet-associated protein (HILPDA) is implicated in OS progression, but its oncogenic mechanisms remain unclear.
• Understanding HILPDA's role is crucial for developing effective OS treatments.

Purpose of the Study:

• To elucidate the oncogenic mechanisms of HILPDA in osteosarcoma.
• To investigate the regulatory relationship between WTAP and HILPDA in OS.
• To explore the potential of the WTAP/HILPDA axis as a therapeutic target.

Main Methods:

• Assessed glycolytic activity (glucose uptake, lactate release) and ferroptosis markers (ROS, MDA, iron content).
• Evaluated cell proliferation (EdU assay), angiogenesis (HUVEC tube formation), and in vivo tumor growth (xenografts).
• Utilized quantitative PCR, immunoblotting, immunohistochemistry, and MeRIP assay to analyze gene expression and m6A modification.

Main Results:

• HILPDA and WTAP were upregulated in OS tissues and associated with poor prognosis.
• HILPDA deficiency reduced OS cell proliferation and glycolysis, induced ferroptosis, and inhibited angiogenesis.
• WTAP regulated HILPDA expression via an m6A-dependent mechanism, and HILPDA re-expression reversed WTAP knockdown effects.

Conclusions:

• The WTAP/HILPDA axis is a key regulator of osteosarcoma development.
• This axis coordinates glycolysis, ferroptosis, and angiogenesis in OS.
• Targeting the WTAP/HILPDA pathway presents a promising multi-targeted therapeutic strategy for osteosarcoma.