From RCT to mechanistic study: ATRA reverses myofibroblast activation by reprogramming glucose metabolism via HIC1 and PCK1/2 to attenuate hypertrophic scar formation.

Summary

A multicenter double-blind RCT found tretinoin cream non-inferior to silicone gel for preventing hypertrophic scars and reducing scar thickness. Mechanistic multi-omics showed ATRA activates RARα to upregulate HIC1, PCK1, and PCK2, suppressing aerobic glycolysis and myofibroblast activation; in vivo overexpression of these targets reduced scarring in mice.

Key Findings

• In a multicenter double-blind RCT, tretinoin cream was non-inferior to silicone gel for preventing hypertrophic scarring (absolute risk difference −8.65%, 90% CI −23.03 to 5.74).
• ATRA reduced hypertrophic scar formation in mouse and rabbit models without impairing normal wound healing.
• Mechanistically, ATRA via RARα upregulated HIC1, PCK1, and PCK2, suppressing aerobic glycolysis, limiting myofibroblast activation, and reducing fibroblast proliferation.
• Fibroblast-specific overexpression of HIC1, PCK1, or PCK2 in Col1a2-CreER mice significantly attenuated myofibroblast activation and hypertrophic scarring.

Clinical Implications

Topical tretinoin can be considered for hypertrophic scar prophylaxis after wounds or procedures, and the ATRA/RARα–HIC1–PCK1/2 axis offers a mechanistic basis for metabolic antifibrotic strategies.

Limitations

• Human sample size and detailed demographics were not specified in the abstract.
• Long-term clinical outcomes and performance across diverse skin types require further study.

Future Directions

Larger, diverse RCTs assessing long-term scar outcomes and patient-reported measures; development of metabolic modulators targeting the RARα–HIC1–PCK1/2 pathway.