Fig. 5. Overview of cellular metabolism and myofibroblast contraction cascades.

Soft ECM causes signalling through the Rho-mDia axis, which is often paired with the assembly of actin filaments and upregulation of the mevalonate pathway. Additionally, the same integrin receptors can bind the latency complex of TGF-β thereby causing release of the mature ligand. This, together with YAP/TAZ, then takes over the actin filament synthesis and by increasing the expression of key enzymes in the glycolysis and glutaminolysis the TGF-β and YAP/TAZ axis produce stiffer ECM. Stiff ECM causes the integrin signalling to shift to the Rho-ROCK axis, which is paired with myosin II synthesis and subsequently contraction. Additionally, ROCK promotes YAP/TAZ to be localised in the nucleus to promote a feedforward loop towards stiff ECM and myofibroblast contraction. By inhibiting key points in the feedforward loop, such as the mevalonate pathway with statins^109–112, glycolysis with Anlotinib¹⁰⁴, lactate production by GSK2837808A¹⁰⁶, or glutaminolysis with BPTES^107,108, it might be possible to break the loop and thereby switch the fibrotic cascades back to regenerative cascades.