Control of fibrosis and hypertrophic scar formation via glycolysis regulation with IR780

Abstract

Background Hypertrophic scars (HS) represent one of the most common clinical challenges due to unsatisfactory therapeutic results. HS formation is associated with the abnormal activation of fibroblasts and their excessive fibrotic behavior. Glycolysis dysregulation has been shown to participate in the incidence and progression of various fibrotic diseases and shows potential as a means of controlling HS formation. This work aimed to discuss the impact of augmented glycolysis on HS and to propose a method for controlling HS formation through glycolysis regulation. Methods Here, augmented glycolysis was confirmed together with enhanced fibrotic activity in both HS fibroblasts (HFs) and HS tissues, and the suppression of glycolysis also attenuated fibroblast activation. We also introduced IR780, a heptamethine cyanine dye, to regulate glycolysis for the control of HS formation. Results In vitro, cell studies indicated that IR780 significantly down-regulated glycolysis and suppressed the fibrotic activity of HFs. In vivo, the intralesional injection of IR780 into rabbit HS models led to the downregulation of glycolysis and the control of HS formation. Furthermore, IR780 accumulated preferentially in activated fibroblasts in both in vitro and in vivo studies, and thus specifically downregulated glycolysis and efficiently controlled fibrosis by targeting activated fibroblasts. Conclusions This work identified a strategy for controlling fibrosis and HS formation from the perspective of glycolysis regulation with IR780 targeting of activated fibroblasts.

Inhibition of phosphatidylinositol 3-kinase catalytic subunit alpha by miR-203a-3p reduces hypertrophic scar formation via phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway

“…After regional injection of miR-203a-3p, the scar appearance was noticeably improved, while the cross-sectional area, scar elevation index, collagen density and scar index were significantly decreased, indicating that miR-203a-3p improved the morphology and histological phenotypes of scars in vivo [ 47 ]. Previous studies have shown that α-SMA is highly expressed in fibrotic disease-derived myofibroblasts [ 48 , 49 ]. Our IHC results also showed a significant reduction in α-SMA in miR-203a-3p-treated scars, suggesting that miR-203a-3p inhibited fibroblasts transdifferentiation in vivo .…”

Integrative Analysis of Lactylome and Proteome of Hypertrophic Scar To Identify Pathways or Proteins Associated with Disease Development

“…The levels of Kla were found to be significantly lower in hypertrophic scar tissues and fibroblasts than in normal skin tissues and fibroblasts. However, previous reports have indicated the presence of augmented glycolysis and lactate accumulation in hypertrophic scar fibroblasts (HSF) and hypertrophic scar (HS) tissues . This discrepancy may be attributed to variations in the samples used.…”

“…Augmented glycolysis has been confirmed in HS and is essential for the excessive fibrotic behavior exhibited by HS fibroblasts . In this study, we identified numerous lactylation sites on enzymes involved in glycolysis/gluconeogenesis.…”

“…Recently discovered in 2019 through mass spectrometry, lactylation, a PTM involving the lactate-derived lysine residue lactylation (Kla), has been observed on both histones and nonhistones. This modification plays a critical role in various physiological and pathophysiological processes, such as the regulation of metabolism, wound healing, and carcinogenesis. − The biological significance of Kla in the hypertrophic scar is currently not well understood, despite the confirmation of augmented glycolysis and lactate accumulation in hypertrophic scar fibroblasts (HSF) and hypertrophic scar (HS) tissues …”

Fibroblast heterogeneity: Keystone of tissue homeostasis and pathology in inflammation and ageing

“…In addition to the epigenetic machinery, strategies that target the imbalanced metabolic pathways in both RA SFs and CAFs have been employed to reduce RA severity and inhibit tumour growth respectively (158,159)). Interestingly, a recent study proposes a new strategy to control fibrosis and hypertrophic scars formation using an anti-glycolytic agent that regulates fibroblasts activity (160). Glycolysis inhibition has also been shown to reduce cardiac fibroblasts activation in-vitro and to control cardiac fibrosis in mice with myocardial infarction (69).…”