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

Zi-Chao Li; Yi-Fu Zhu; Ya-Juan Song; Zhi-Jun Tan; Bin Liu; Yan Jiang; Hou-An Xiao; Dong-Mei Zu; Tong Wang; Yi Shi; Yan Jiao; Xue-Yong Li; Xing-Bo Xu; Lei Shang; Zhou Yu; Bao-Qiang Song

doi:10.1016/j.mmr.2026.100021

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

RESEARCH | Updated：2026-05-11

- From RCT to mechanistic study: ATRA reverses myofibroblast activation by reprogramming glucose metabolism via HIC1 and PCK1/2 to attenuate hypertrophic scar formation
- Military Medical Research (2026)
- Affiliations：
  
  Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
  Department of Plastic and Aesthetic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
  Department of Health Statistics, Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi’an 710032, China
  Department of Burn, Plastic and Cosmetic Surgery, Xi’an Central Hospital, Xi’an Jiaotong University, Xi’an 710003, China
  Department of Cosmetology, the Second People’s Hospital of Jiangyou City, Jiangyou 621702, Sichuan, China
  Department of Burns, Plastic and Cosmetic Surgery, Xian Ninth Hospital, Xi’an 710054, China
  Department of Plastic Surgery, People’s Hospital of Ankang City, Ankang 725000, Shaanxi, China
  Department of Burn and Plastic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China
  Department of Burn and Plastic Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, China
  Clinic for Cardiology and Pulmonology, University Medical Center Göttingen, Göttingen 37075, Germany
- Author bio：
  
  Xing-Bo Xu, xingbo.xu@med.uni-goettingen.de;
  *Lei Shang, Shanglei@fmmu.edu.cn;
  Zhou Yu, yz20080512@163.com;
  Bao-Qiang Song, songbq2012@163.com
- Funds：
- DOI：10.1016/j.mmr.2026.100021
  CLC：
- Received：08 June 2025，
  
  Accepted：16 March 2026，
  
  Published：2026-04
- Accepted：
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Li ZC, Zhu YF, Song YJ, Tan ZJ, Liu B, Jiang Y, et al. From RCT to mechanistic study: ATRA reverses myofibroblast activation by reprogramming glucose metabolism via HIC1 and PCK1/2 to attenuate hypertrophic scar formation. Mil Med Res. 2026;13(1):100021.
DOI：

Li ZC, Zhu YF, Song YJ, Tan ZJ, Liu B, Jiang Y, et al. From RCT to mechanistic study: ATRA reverses myofibroblast activation by reprogramming glucose metabolism via HIC1 and PCK1/2 to attenuate hypertrophic scar formation. Mil Med Res. 2026;13(1):100021. DOI： 10.1016/j.mmr.2026.100021.

摘要

Abstract

Background:

Abnormal glucose metabolism often contributes to myofibroblast activation and the pathogenesis of skin fibrotic diseases. All-trans retinoic acid (ATRA)

the active component of tretinoin cream

can regulate glucose metabolism and activate myofibroblasts. Importantly

investigating the potential of ATRA to inhibit myofibroblast activation by modulating glucose metabolism could reveal the translational significance of ATRA in attenuating hypertrophic scar (HS) formation.

Methods:

We first conducted a multicenter

double-blind

randomized controlled trial (RCT) to compare the effects of tretinoin cream with those of the first-line medication

silicone gel. In the mechanistic study

the characteristics of glucose metabolic reprogramming and the activation of hypertrophic scar fibroblasts (HSFs) after ATRA treatment were identified through multi-omics profiling

complemented by glucose metabolism assays and functional validations. Besides

genetic overexpression targeting the potential downstream molecules of ATRA

including hypermethylated in cancer 1 (HIC1)

phosphoenolpyruvate carboxykinase (PCK)1

and PCK2

was conducted

in vitro

in HSFs and

in vivo

in skin fibroblasts of Col1a2-CreER mice.

Results:

Our RCT demonstrated that tretinoin cream is non-inferior to silicone gel in preventing HS formation

with the absdute risk difference of incidence rates [–8.65% 90% two-sided (confidence interval) CI –23.03 to 5.74] and in decreasing scar thickness [(2856.20±211.83) μm vs. (1664.57±273.50) μm]

attributing to the reduction in HSF proliferation and the proportion of myofibroblasts. Moreover

tretinoin cream effectively mitigated HS formation in both mice and rabbits without impeding normal wound healing. Mechanistically

HSFs underwent glucose reprogramming

characterized by increased aerobic glycolysis

which facilitated the transition of HSFs to myofibroblasts and their proliferation. However

ATRA upregulated HIC1

PCK1

and PCK2 expression through retinoic acid receptor alpha (RARα) activation

thereby inhibiting the fibrotic phenotypes of HSFs by suppressing aerobic glycolysis and facilitating gluconeogenesis. The fibroblast-specific overexpression of HIC1

PCK1

or PCK2 in Col1a2-CreER mice significantly reduced myofibroblast activation and hypertrophic scarring.

Conclusions:

Our study not only substantiated that topical tretinoin cream could serve as an effective strategy to prevent HSs in clinical settings

but also established ATRA as a regulator of glucose metabolism. Importantly

ATRA/RARα-mediated glucose reprogramming was identified as a potential therapeutic target for attenuating HS formation.

关键词

Keywords

references

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