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Emerging evidence suggests that ion channels, transporters, and pumps\u2014the transportome\u2014have 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\n                    <jats:sup>+<\/jats:sup>\n                    , and cystic fibrosis transmembrane regulator (CFTR) channels; the Na\n                    <jats:sup>+<\/jats:sup>\n                    \/H\n                    <jats:sup>+<\/jats:sup>\n                    exchanger NHE1; and the Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    -ATPase. By comparing analogous pathways across different fibrotic diseases such as Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling and transforming growth factor \u03b21 (TGF-\u03b21) and Wnt\/\u03b2-catenin pathways, we highlight the druggable potential of these ion transport proteins and suggest novel concepts for therapeutic intervention.\n                  <\/jats:p>","DOI":"10.1152\/ajpcell.00564.2025","type":"journal-article","created":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:30:48Z","timestamp":1760113848000},"page":"C2091-C2111","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["A tough job: ion channels, transporters, and pumps during organ fibrosis"],"prefix":"10.1152","volume":"329","author":[{"given":"Weronika","family":"Wilczak","sequence":"first","affiliation":[{"name":"University of 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