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. Author manuscript; available in PMC: 2026 Jun 15.
Published in final edited form as: Nat Rev Drug Discov. 2025 Mar 18;24(7):543–569. doi: 10.1038/s41573-025-01158-9

Fig. 2 |. Myofibroblast activation states and pathways.

Fig. 2 |

Key pathways that regulate fibroblast-to-myofibroblast activation, described from left to right of the figure. Fibroblastic cells secrete transforming growth factor-β1 (TGFβ1) in complex with its latency-associated pro-peptide (LAP), which can bind to latent TGFβ1 binding proteins (LTBPs) in the extracellular matrix (ECM). Stiff fibrotic ECM resists cell forces transmitted to LAP via αv integrins that mechanically liberate active TGFβ1. TGFβ1 binding to its receptor triggers canonical SMAD signalling, driving the transcription of profibrotic genes. Another TGFβ1 signalling pathway is activation of the Rho–Rho-associated protein kinase (ROCK), which is also mediated through G protein-coupled receptors (GPCRs) upon binding of lysophosphatidic acid (LPA) and/or thrombin. GPCR activity produces active (GTP-bound) RhoA by regulating guanidine nucleotide exchange factors (GEFs). Active RhoA–ROCK drive fibroblast contraction by inhibiting myosin light chain (MLC) phosphatase (MLCP) and activating myosin light chain kinase (MLCK). MLCK is also activated by cytosolic calcium elevations; for instance, following stretch-induced opening of Piezo1 or transient receptor potential vanilloid 4 (TRPV4) ion channels. Additionally, activation of integrin signalling — for example, through focal adhesion kinase (FAK) — results in the polymerization of globular into filamentous (F-) actin. High levels of F-actin and active RhoA inhibit the Hippo signalling components large tumour suppressor kinases LATS1 and LATS2, ultimately resulting in dephosphorylation and nuclear translocation of Yes-associated protein 1 (YAP) and PDZ-binding motif (TAZ) co-transcription factors, whereby they drive the transcription of profibrotic genes; phosphorylated YAP and TAZ undergo proteasomal degradation in the cytosol. Furthermore, actin polymerization releases myocardin-related transcription factor A (MRTFA) from bound G-actin to translocate to the nucleus and drive profibrotic gene products. Although SMADs, YAP/TAZ and MRTFA all regulate the transcription of profibrotic genes, they occupy different promoter regions and engage different co-transcription factors. αSMA, α-smooth muscle actin; P, phosphate.