A tough job: ion channels, transporters, and pumps during organ fibrosis.

Fibrosis plays a crucial role in a range of chronic diseases, including cancer. Emerging evidence suggests that ion channels, transporters, and pumps-the transportome-have an essential share in fibrogenesis and fibrosis by regulating fibroblast and myofibroblast activity. This review bridges current knowledge gaps by integrating insights from multiple diseases affecting the heart, lungs, pancreas, kidney, and liver, as well as cancer. Thereby, we reveal shared molecular mechanisms of how the transportome modulates fibroblast activation, extracellular matrix deposition, tissue stiffness, and remodeling. We focus on the roles of various ion transport proteins, including PIEZO1, transient receptor potential (TRP), K+, and cystic fibrosis transmembrane regulator (CFTR) channels; the Na+/H+ exchanger NHE1; and the Na+/K+-ATPase. By comparing analogous pathways across different fibrotic diseases such as Ca2+ signaling and transforming growth factor β1 (TGF-β1) and Wnt/β-catenin pathways, we highlight the druggable potential of these ion transport proteins and suggest novel concepts for therapeutic intervention.