Work

Differentiation arrest of transitional alveolar epithelial cells drives pulmonary fibrosis

Year: 2026

Type: article

Abstract: Alveolar epithelial type 2 cells (AEC2) serve as facultative stem cells of the lung, differentiating into type 1 cells (AEC1) to restore barrier integrity after injury. Recent single-cell studies have identified a transient Krt8 + transitional state as an essential intermediate in this process. In idiopathic pulmonary fibrosis (IPF), however, this program is disrupted, leading to the persistence of cells trapped in a differentiation block. These maladaptive cells act not only as markers of failed regeneration but also as active profibrotic signaling hubs that amplify disease progression. Here, we synthesize current evidence on the molecular mechanisms underlying this arrest, including dysregulated signaling pathways (Wnt, YAP/TAZ, Notch), metabolic reprogramming, and epigenetic constraints. We further discuss how these cells remodel the microenvironment and interact with stromal compartments to sustain a self-reinforcing profibrotic niche. Targeting this upstream epithelial arrest may offer a promising therapeutic strategy for pulmonary fibrosis.

Source: Cell Communication and Signaling

DOI: 10.1186/s12964-026-03163-w

Authors: Haotian Cheng, Ruiyan Liu, Yan Zhou, Bo Zhang

Institutions: Central South University, Xiangya Hospital Central South University

Language: English

Topic: Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,390