Melatonin inhibits fibroblast cell functions and hypertrophic scar formation by enhancing autophagy through the MT2 receptor-inhibited PI3K/Akt /mTOR signaling.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
melatonin treatment | decrease | migration capacity | primary fibroblasts from human HS (HSFs) | - | significantly decreased | #1 |
melatonin treatment | decrease | contraction capacity | primary fibroblasts from human HS (HSFs) | - | significantly decreased | #2 |
melatonin treatment | decrease | collagen production | primary fibroblasts from human HS (HSFs) | - | significantly decreased | #3 |
melatonin treatment | decrease | α-smooth muscle actin (α-SMA) production | primary fibroblasts from human HS (HSFs) | - | significantly decreased | #4 |
melatonin treatment | neutral | expression of genes involved in autophagy and oxidative stress | primary fibroblasts from human HS (HSFs) | - | modulated | #5 |
melatonin treatment | decrease | AKT/mTOR activation | primary fibroblasts from human HS (HSFs) | - | attenuated | #6 |
melatonin treatment | increase | autophagy | primary fibroblasts from human HS (HSFs) | - | enhance | #7 |
melatonin treatment | decrease | fibrogenic factor production | primary fibroblasts from human HS (HSFs) | - | decreasing | #8 |
melatonin treatment | decrease | HS formation | rabbit ears | - | inhibited | #9 |
melatonin treatment | increase | autophagy | rabbit ears | - | enhancing | #10 |
treatment with an autophagy inhibitor (3-methyladenine, 3-MA) | neutral | anti-fibrotic effects of melatonin | - | - | abrogated | #11 |
treatment with an Akt activator (SC79) | neutral | anti-fibrotic effects of melatonin | - | - | abrogated | #12 |
treatment with an MT2 selective antagonist (4-phenyl-2propionamidotetralin, 4-P-PDOT) | neutral | anti-fibrotic effects of melatonin | - | - | abrogated | #13 |
Hypertrophic scar (HS) is a fibrotic skin condition and characterized by abnormal proliferation of myofibroblasts and accumulation of extracellular matrix. Melatonin, an endogenous hormone, can alleviate fibrosis in multiple models of diseases. This study examined the effect of melatonin on fibrosis in primary fibroblasts from human HS (HSFs) and a rabbit ear model and potential mechanisms. Melatonin treatment significantly decreased the migration and contraction capacity, collagen and α-smooth muscle actin (α-SMA) production in HSFs. RNA-sequencing and bioinformatic analyses indicated that melatonin modulated the expression of genes involved in autophagy and oxidative stress. Mechanistically, melatonin treatment attenuated the AKT/mTOR activation through affecting the binding of MT2 receptor with PI3K to enhance autophagy, decreasing fibrogenic factor production in HSFs. Moreover, melatonin treatment inhibited HS formation in rabbit ears by enhancing autophagy. The anti-fibrotic effects of melatonin were abrogated by treatment with an autophagy inhibitor (3-methyladenine, 3-MA), an Akt activator (SC79), or an MT2 selective antagonist (4-phenyl-2propionamidotetralin, 4-P-PDOT). Therefore, melatonin may be a potential drug for prevention and treatment of HS.