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Updated: Jul 11, 2026
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
From RCT to mechanistic study: ATRA reverses myofibroblast activation by reprogramming glucose metabolism via HIC1
Zi-Chao Li1,2, Yi-Fu Zhu1, Ya-Juan Song1
1Department of Plastic Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
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 absolute 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.
Trial Registration:
ChiCTR, ChiCTR2500097242. Registered on 14 Feb, 2025. Available from https://www.chictr.org.cn/bin/project/edit?pid=220146.
Insights
Tretinoin cream is as effective as silicone gel in preventing hypertrophic scars by modulating glucose metabolism. All-trans retinoic acid (ATRA) targets glucose reprogramming in fibroblasts, offering a new therapeutic approach for scar reduction.
Area of Science:
- Dermatology and Cutaneous Biology
- Metabolic Regulation in Fibrotic Diseases
- Wound Healing and Scarring Research
Background:
- Abnormal glucose metabolism is linked to myofibroblast activation and skin fibrotic diseases.
- All-trans retinoic acid (ATRA), found in tretinoin cream, influences glucose metabolism and myofibroblast activity.
- Investigating ATRA's effect on glucose metabolism could offer new strategies for hypertrophic scar (HS) prevention.
Purpose of the Study:
- To compare the efficacy of tretinoin cream versus silicone gel in preventing hypertrophic scar formation.
- To elucidate the mechanistic role of ATRA in modulating glucose metabolism and myofibroblast activation in HS pathogenesis.
- To identify potential therapeutic targets for attenuating HS formation through ATRA-mediated metabolic regulation.
Main Methods:
- A multicenter, double-blind, randomized controlled trial (RCT) comparing tretinoin cream with silicone gel.
- Multi-omics profiling, glucose metabolism assays, and functional validation to study ATRA's effects on hypertrophic scar fibroblasts (HSFs).
- In vitro and in vivo genetic overexpression of downstream ATRA molecules (HIC1, PCK1, PCK2) in fibroblasts.
Main Results:
- Tretinoin cream demonstrated non-inferiority to silicone gel in preventing HS formation and reducing scar thickness.
- ATRA upregulated HIC1, PCK1, and PCK2 expression via RARα activation, suppressing aerobic glycolysis and promoting gluconeogenesis in HSFs.
- Fibroblast-specific overexpression of HIC1, PCK1, or PCK2 significantly reduced myofibroblast activation and hypertrophic scarring in vivo.
Conclusions:
- Topical tretinoin cream is an effective strategy for preventing hypertrophic scars in clinical settings.
- ATRA acts as a regulator of glucose metabolism, offering a novel therapeutic target for HS attenuation.
- ATRA/RARα-mediated glucose reprogramming presents a promising pathway for managing hypertrophic scar formation.
