Cellular senescence refers to a state of irreversible cell cycle arrest triggered by various stressors, including oxidative damage, genomic instability, and telomere attrition [1]. Senescent cells exhibit distinct morphological alterations, including increased cell size, a flattened shape, multinucleation, cytoplasmic vacuolization, and loss of normal physiological functions [2], [3]. These cells actively secrete a spectrum of pro-inflammatory chemokines, cytokines, growth factors, and matrix-degrading enzymes collectively defined as the senescence-associated secretory phenotype (SASP). While initially being protective by preventing the replication of damaged cells, its chronic persistence, primarily via SASP, can drive sustained inflammation and impair tissue homeostasis [4], [5], [6], [7], [8], [9].

Idiopathic pulmonary fibrosis (IPF) is a widespread chronic interstitial lung disease marked by aberrant wound-healing responses to recurrent alveolar epithelial injury [10], [11]. Central to this fibrotic remodeling process is the transforming growth factor-beta (TGF-β) signaling pathway, which governs several cellular processes underlying disease initiation and progression [12], [13], [14]. Under physiological conditions, TGF-β serves as a multifaceted cytokine that orchestrates cell proliferation, programmed death, differentiation, and extracellular matrix (ECM) synthesis to maintain tissue architecture. In contrast, under disease situations such as in IPF, chronic or hyper-activation of TGF-β signaling promotes repetitive myofibroblast differentiation and ECM accumulation that leads to irreversible scarring and derangement of lung parenchyma [15], [16]. Moreover, the fibrogenic effects of TGF-β are amplified by its interaction with other signaling networks, such as Wnt/β-catenin, MAPK, and PI3K/Akt pathways, complicating the therapeutic landscape for targeting fibrosis [17]. TGF-β signaling not only orchestrates fibrotic remodeling but also exacerbates the pathological decline seen in age-related conditions such as Alzheimer’s disease, Parkinson’s disease, and sarcopenia, underscoring its broad impact beyond PF [18], [19], [20], [21].

Cellular senescence has long been implicated in the age-related decline in regenerative capacity and the pathogenesis of conditions such as IPF [8], [22]. The progression from cellular senescence to fibrotic scarring is a highly intricate and multifactorial biological cascade that drives tissue remodeling [23]. TGF-β signaling is recognized as a central regulator of fibrosis and a potent inducer of senescence, highlighting its dual role in PF. In the fibrotic lung, both TGF-β signaling and cellular senescence are consistently implicated, suggesting that their interaction may form a self-reinforcing feedback loop that accelerates disease onset and progression. This review examines the crosstalk between TGF-β and senescence, illustrating how their convergence drives fibrotic remodeling and disease progression. Additionally, it discusses emerging biomarkers, senotherapeutic strategies, and TGF-β–targeted interventions with translational potential, integrating mechanistic and clinical insights to guide the development of targeted therapies for PF.