Metabolic Regulation of Fibroblast Activation and Proliferation during Organ Fibrosis

Abstract

<b><i>Background:</i></b> Activated fibroblasts are present in the injury response, tumorigenesis, fibrosis, and inflammation in a variety of tissues and myriad disease types. <b><i>Summary:</i></b> During normal tissue repair, quiescent fibroblasts transform into a proliferative and contractile phenotype termed myofibroblasts and are then lost as repair resolves to form a scar. When excessive levels are reached, activated fibroblasts proliferate and produce large amounts of extracellular matrix, which accumulates in the interstitial space of different organs. This accumulation leads to fibrotic dysfunction and multiple-organ dysfunction syndrome. To date, there are limited effective treatments for these conditions. Cellular metabolism is the cornerstone of all biological activities. Emerging evidence shows that metabolic alterations in fibroblasts are important for the activation process and illness progression. These discoveries, along with current clinical advances showing decreased lung fibrosis after targeting specific metabolic pathways, thus offer new possibilities for therapeutic interventions. The purpose of this review was to summarize the most recent knowledge of the major metabolic changes that occur during fibroblast transition from quiescent to activated states and the evidence linking alterations in fibroblast metabolism to the pathobiology of several common fibrotic diseases and tumor-related diseases. <b><i>Key Messages:</i></b> Metabolic disorders are associated with the progression of chronic kidney diseases. Interfering with fibroblast metabolism may be a promising therapeutic strategy for renal fibrosis and other fibrosis-related diseases.

Increased glycolysis and cellular crosstalk in eosinophilic chronic rhinosinusitis with nasal polyps

“…Furthermore, glycolytic gene expression was positively correlated with ECM remodeling gene sets in fibroblasts and endothelial cells, specifically with gene sets involving collagen synthesis ( Figures 3B, C ). This is consistent with prior reports which have nominated inhibition of fibroblast glycolysis as a therapeutic target for treatment of fibrotic diseases ( 39 ) and studies demonstrating that inhibition of endothelial cell glycolysis can decrease endothelial proliferation and recruitment of inflammatory cells ( 40 , 41 ). Interestingly, the positive correlation between glycolysis and the Reactome collagen formation gene set in endothelial cells appeared to be driven by COL15A1 and COL18A1 ( Figure 3C ), both collagens which can be proteolytically cleaved to release signaling domains that regulate angiogenesis ( 42 , 43 ).…”

Targeted delivery of galunisertib using machine perfusion reduces fibrogenesis in an integrated ex vivo renal transplant and fibrogenesis model

“…Not to forget, fibrogenesis requires an increased energy demand for fibroblast proliferation and protein synthesis (Wang et al, 2022), a process that is suppressed by galunisertib.…”

“…We speculate that these high ATP levels are due to improved cellular respiration during normothermic machine perfusion or the fact that galunisertib is a competitive inhibitor for ATP‐binding site of the TGFβ1 (Yingling et al, 2018). Not to forget, fibrogenesis requires an increased energy demand for fibroblast proliferation and protein synthesis (Wang et al, 2022), a process that is suppressed by galunisertib.…”

Fibrosis Development Linked to Alterations in Glucose and Energy Metabolism and Prooxidant–Antioxidant Balance in Experimental Models of Liver Injury

“…Metabolic changes are crucial for the development of fibrotic changes [ 47 ]. The production of compounds that are structural components of the extracellular matrix is an energy-consuming process, and glycolysis is one of the predominant metabolic pathways in fibroblasts of various organs, including the liver [ 48 ].…”