Figure 5. Metabolic inputs regulating the biosynthetic and transcriptional changes coordinating myofibroblast differentiation.

General schematic of myofibroblast metabolism on the differentiation program. Myofibroblasts are characterized by an increase in glutaminolysis and aerobic glycolysis, accompanied by decreased glucose oxidation. These key metabolic re-programming events permit the use of carbon intermediates by ancillary biosynthetic pathways to coordinate the production of ECM constituents, protein modifications, and epigenetic cofactors that initiate and sustain the myofibroblast differentiation program. Changes in the expression/activity of noted enzymes along with metabolites in bold are key to the differentiation process. Of these processes, the ability of these key metabolites to act as cofactors for epigenetic modifying enzymes is critical for the coordinated activation and silencing of transcriptional events which promote the fibrotic gene program and myofibroblast differentiation/persistence. αKG – α-ketoglutarate; Pyr – pyruvate; HK – hexokinase; PFK – phosphofructokinase; PFKFB3 – 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; PHGDH – phosphoglycerate dehydrogenase; PSAT – phosphoserine amino transferase; PSPH – phosphoserine phosphatase; PKM – pyruvate kinase muscle isozyme; LDH – lactate dehydrogenase; SHMT – serine hydroxymethyltransferase; PDH – pyruvate dehydrogenase; ACLY – ATP citrate lyase; HATs – histone acetyltransferases; HDACs – histone deacetylases; HMT – histone methyltransferases; JmJCs – Jumonji C-domain-containing histone demethylases; DNMTs – DNA methyltransferases; TETs – ten-eleven translocases; Ac – acetylation mark; Me – methylation mark; Lac – lactylation mark.