From senescence to scarring: Exploring TGF-β signaling in cellular aging, fibrotic remodeling, and pulmonary fibrosis

Cellular senescence and the formation of fibrotic scarring are critical in the progression of chronic illnesses, such as pulmonary fibrosis (PF). In this context, the transforming growth factor-beta (TGF-β) pathway represents a central driver in orchestrating the pathological cascade. TGF-β governs cellular activities such as differentiation, apoptosis, and extracellular matrix (ECM) remodeling as a pleiotropic cytokine. In the lungs, dysregulated TGF-β signaling leads to cellular senescence and release of pro-inflammatory mediators, constituting the senescence-associated secretory phenotype (SASP). This reinforces a microenvironment conducive to fibroblast activation, prolonged myofibroblast retention, and accelerated aberrant ECM deposition, culminating in progressive tissue fibrosis. For instance, idiopathic pulmonary fibrosis (IPF) is marked by the buildup of senescent alveolar epithelial cells (AECs) that impair regular tissue repair and alter the microenvironment to promote fibrogenesis. TGF-β signaling is activated through SMAD-dependent (canonical) and SMAD-independent (non-canonical) pathways, each contributing to the persistence of activated fibroblasts, aberrant ECM accumulation, and irreversible tissue remodeling. The interdependence between senescence and TGF-β signaling perpetuates fibrotic injury and enhances susceptibility to future fibrotic insults. This review delves into understanding the molecular convergence of TGF-β signaling and cellular senescence in PF, highlighting key biomarkers and emerging therapeutic strategies. While several clinical trials evaluating TGF-β antagonists, small molecules, and cell-based therapies show considerable promise, challenges remain regarding their successful translation into effective, targeted treatments. Nevertheless, continued exploration of TGF-β’s multifaceted role in fibrosis and senescence offers hope for developing innovative therapies for PF and other chronic fibrotic diseases.