METTL16 Modulates GPX4 Expression to Regulate Chondrocyte Ferroptosis.

Area of Science:

• Epigenetics
• Molecular Biology
• Skeletal Dysplasias

Background:

• Achondroplasia (ACH) is a genetic disorder causing disproportionate short stature, linked to fibroblast growth factor receptor 3 (FGFR3) mutations.
• N6-methyladenosine (m⁶A) RNA modification influences mRNA stability and translation.
• The role of METTL16, an m⁶A methyltransferase, in ACH pathophysiology was investigated.

Purpose of the Study:

• To explore the epigenetic regulatory function of METTL16 in achondroplasia.
• To investigate the impact of METTL16 on chondrocyte function and ferroptosis in ACH.
• To elucidate the molecular mechanism underlying METTL16's effect on bone development in ACH.

Main Methods:

• Generated an achondroplasia mouse model (Fgfr3^ach).
• Analyzed chondrocyte proliferation, viability, and ferroptosis markers (Fe²⁺, MDA, GSH).
• Assessed bone structure (BMD, BV/TV, TbN, TbTh), gene/protein expression (qPCR, Western blot), and m⁶A modification levels.

Main Results:

• METTL16 overexpression improved bone chondrogenesis and chondrocyte proliferation in the ACH model.
• METTL16 reduced ferroptosis in vitro and in vivo by increasing glutathione peroxidase 4 (GPX4) expression.
• METTL16 enhanced m⁶A modification of GPX4 mRNA, suppressing its degradation; GPX4 depletion negated METTL16's effects.

Conclusions:

• METTL16 overexpression promotes bone growth and alleviates chondrocyte ferroptosis in ACH.
• The METTL16/GPX4 axis, via m⁶A modification of GPX4 mRNA, is a key mechanism.
• The METTL16/GPX4 pathway presents a potential therapeutic target for achondroplasia treatment.