Research on Alveolar Type II Epithelial Cell Senescence in Idiopathic Pulmonary Fibrosis

Lichun Zhong^1,#, Dijia Wu^2,#, Sirui Zhang², Wenjing Liu², Faping Wang^3,*, Fengming Luo^3,*
1 Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
2 West China School of Clinical Medicine, West China Hospital, Sichuan University, Chengdu, China
3 Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
* Corresponding Author: Faping Wang. Email: email ; Fengming Luo. Email: email
# These authors contributed equally to this work
(This article belongs to the Special Issue: Autophagy and Oxidative Stress in Cancer: Molecular Crossroads and Cell Fate Decisions)

BIOCELL https://doi.org/10.32604/biocell.2026.078898

Received 10 January 2026; Accepted 11 May 2026; Published online 29 May 2026

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Abstract

Idiopathic pulmonary fibrosis (IPF) is an age-associated, progressive fibrotic interstitial lung disease with limited disease-modifying therapies and poor long-term outcomes. Increasing evidence indicates that senescence of alveolar type II epithelial (AT2) cells is not merely a bystander phenomenon but a central driver of epithelial dysfunction, failed alveolar regeneration, and fibrotic remodeling. In this narrative review, we summarize recent mechanistic, single-cell, epigenetic, and translational studies that have reshaped the epithelial-centered model of IPF. We first outline normal AT2 biology and the regenerative AT2-to-AT1 trajectory, and then discuss how telomere dysfunction, endoplasmic reticulum stress, mitochondrial injury, DNA damage signaling, and aberrant mechanotransduction promote AT2 senescence. We further examine how senescence-associated secretory phenotype (SASP), maladaptive transitional epithelial states, and epithelial-stromal crosstalk sustain fibrosis. Finally, we review emerging therapeutic approaches, including senolytics, senomorphics, pathway-directed interventions, and RNA or epigenetic strategies, while emphasizing current limitations in model systems, biomarker development, delivery, safety, and patient stratification. Together, the available evidence supports AT2 senescence as a pathogenic and potentially targetable axis in IPF.