Volume 10 Number 1 2026
Cellular Senescence as a Pathogenic Hub Driving Mechanistic Networks and Reversal Strategies in Idiopathic Pulmonary Fibrosis
Sakina Ruhi 1*, Adlina Abdullatif 1, Jegathambigai R. Naidu 1, Hana Chen 1, Ayesha Syed 1, Danish Saud khan 2, Husni Ahmed Al Gosha 1
Integrative Biomedical Research 10 (1) 1-25 https://doi.org/10.25163/biomedical.10110925
Submitted: 20 June 2026 Revised: 12 August 2026 Accepted: 21 August 2026 Published: 23 August 2026
Idiopathic pulmonary fibrosis (IPF) is a progressive, ultimately fatal interstitial lung disease for which current antifibrotic therapy — pirfenidone and nintedanib — can slow but not reverse the underlying scarring process, leaving median survival at only three to five years. Over the past several years, the field's understanding of IPF has shifted from a chronic-inflammatory model toward one centered on epithelial injury and, more specifically, on the pathological accumulation of senescent cells within the alveolar niche. This review set out to synthesize that literature systematically, tracing how cellular senescence is generated, sustained, and might eventually be reversed in the fibrotic lung. Using a structured, PubMed-anchored search strategy supplemented by citation-chasing, we reviewed preclinical and clinical studies addressing senescent alveolar epithelial cells (particularly AEC2 progenitors and their KRT8? and KRT5?/KRT17? transitional states), heterogeneous CTHRC1? myofibroblast populations, and the intracellular signaling networks — PTEN/Akt/mTOR/NF-κB, Sirt1/HSF1/HSPs, and the senescence–autophagy axis — that govern their behavior. We found converging evidence, across independent injury models, that senescent epithelial and mesenchymal cells sustain fibrogenesis through a persistent senescence-associated secretory phenotype (SASP), reinforced by glycolytic metabolic reprogramming and matrix-stiffness-driven mechanotransduction that together lock the tissue into a self-perpetuating fibrotic state. Emerging senotherapeutic strategies — senolytics (dasatinib plus quercetin), senomorphics (EF24, semaglutide, curculigoside, ISRIB), and, notably, autologous basal cell transplantation — showed encouraging, if still largely preclinical or early-phase, evidence of reducing senescent burden and, in limited pilot data, improving functional outcomes. We conclude that cellular senescence functions as a mechanistic hub linking epithelial failure to mesenchymal activation in IPF, offering a biologically coherent rationale for combination senotherapeutic and regenerative strategies, though substantial translational gaps — disease-specific biomarkers, aging-relevant models, and targeted delivery — remain before these approaches can be tested definitively in patients.
Keywords: Idiopathic pulmonary fibrosis; Cellular senescence; Senescence-associated secretory phenotype (SASP); Senotherapeutics; Alveolar epithelial regeneration; Autophagy–senescence axis; Myofibroblast heterogeneity
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