Targeting fibrosis: unraveling pathogenesis for therapeutic advances

Abstract Organ fibrosis constitutes the final common pathway of chronic progressive diseases, marked by excessive extracellular matrix (ECM) deposition, parenchymal cell loss, and structural disruption that culminate in organ failure across multiple tissues. Its pathogenesis is driven by dysregulated wound-healing responses to sustained injury, involving intricate crosstalk among fibroblasts, immune cells, and epithelial cells. The TGF-β/Smad axis operates as the core profibrotic hub, with interconnected Wnt/β-catenin, Hippo/YAP/TAZ, PI3K/AKT, JAK/STAT, and MAPK cascades converging to amplify fibrotic signaling. In parallel, epigenetic remodeling-encompassing non-coding RNA networks, m6A RNA methylation, and DNA/histone modifications-exerts profound regulatory control over profibrotic gene expression, thereby shaping cellular phenotypes and tissue homeostasis. Clinically, fibrosis assessment relies on imaging, circulating biomarkers, and, in selected settings, histopathology. Although disease- and indication-specific therapies are available for certain fibrotic disorders, broadly effective treatments that reverse established fibrosis and restore organ function remain an unmet need. Several small molecule candidates and traditional Chinese medicine formulations are under evaluation, alongside emerging targets including integrin αvβ6, LOXL2, and CTGF. To overcome delivery barriers, novel platforms such as nanoparticle systems, exosomes, liposomes, lipid nanoparticles, inhalable formulations, and microneedle patches are being actively developed for localized and targeted administration. This review synthesizes organ specific pathological features, unifying signaling and epigenetic networks, and emerging therapeutic platforms, while critically assessing translational challenges, with the goal of offering a strategic framework for mechanistic inquiry and antifibrotic drug development.