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Cellular Senescence in Idiopathic Pulmonary Fibrosis: Molecular Mechanisms, Pathogenic Networks, and Emerging Therapeutic Targets

Baurzhan MB, Gulyayev AE, Absattarova KS, Kairgeldina SA, Abzaliyev K, Izbassarova A, Lepessova M, Absatarova K

Diseases (Basel, Switzerland), 2026

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by irreversible extracellular matrix deposition and high mortality, with aging representing its strongest risk factor. Increasing evidence suggests that cellular senescence is not merely a consequence of tissue injury but a central driver of disease progression. Senescent alveolar epithelial cells and fibroblasts contribute to impaired tissue repair and persistent fibrotic remodeling through the acquisition of a senescence-associated secretory phenotype (SASP), which promotes chronic inflammation and amplifies profibrotic signaling. This review provides a comprehensive synthesis of current evidence on the role of cellular senescence in IPF, focusing on key molecular mechanisms, including telomere attrition, mitochondrial dysfunction, oxidative stress, DNA damage response activation, and dysregulated transforming growth factor-β (TGF-β) signaling. A structured literature search was conducted using the PubMed, Scopus, and Web of Science databases to identify mechanistic, translational, and clinical studies related to cellular senescence in IPF. Relevant studies were selected based on conceptual relevance and scientific quality, and findings were qualitatively synthesized within a narrative-review framework. These interconnected pathways form self-reinforcing feedback loops that stabilize the senescent phenotype and sustain fibroblast activation. In addition, we critically…

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