Tissue regeneration: Unraveling strategies for resolving pathological fibrosis

Tissues are constantly exposed to stresses that cause both cellular and structural damage. In response, a coordinated healing process restores tissue integrity and functionality. When these stresses persist or the healing process becomes dysregulated, progressive tissue fibrosis can emerge. This condition is characterized by excessive scarring, disrupted tissue architecture, and loss of organ function. In this review, we explore the relationship between regeneration and fibrosis, with a focus on the lung and liver. We dissect cellular contributions and interplay among fibroblasts, epithelial progenitors, immune components, and vasculature in both regenerative and fibrotic responses to tissue injury. We also examine therapeutic strategies under development that navigate the complexities of immune mediators, fibrogenic myofibroblasts, and excess extracellular matrix (ECM) with small-molecule targeting and various cell-based approaches. By elucidating regulatory networks controlling regeneration and fibrosis, we aim to inform the development of targeted strategies to alleviate or reverse fibrosis, ultimately supporting long-term tissue health.