The pentose phosphate pathway controls oxidative protein folding and prevents ferroptosis in chondrocytes.

Summary

Using chondrocyte-specific G6PD loss, the study shows that PPP-derived NADPH is indispensable to buffer ROS generated during oxidative protein folding. NADPH depletion compromises glutathione recycling, triggers unfolded protein response, induces ferroptosis, and culminates in chondrodysplasia, establishing PPP as a redox gatekeeper of proteostasis in hypoxic cartilage.

Key Findings

• Chondrocyte G6PD loss reduces NADPH, impairing glutathione recycling and protection against ROS generated during oxidative protein folding.
• Proteostasis is disturbed with activation of the unfolded protein response and increased protein degradation.
• Oxidative stress triggers ferroptosis and matrix alterations, producing a chondrodysplasia phenotype, establishing PPP as essential for endochondral ossification.

Clinical Implications

Suggests that enhancing PPP flux or NADPH availability, or targeting ferroptosis pathways, could be explored to improve cartilage resilience in growth disorders and fracture repair.

Limitations

• Preclinical models may not fully capture human cartilage pathophysiology.
• Specific therapeutic interventions modulating PPP/ferroptosis were not tested in disease models.

Future Directions

Evaluate pharmacologic PPP activation or ferroptosis inhibitors in models of growth plate pathology and fracture repair; examine PPP–proteostasis coupling in human cartilage and chondrodysplasia.