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Autophagy‑epithelial‑mesenchymal transition crosstalk in acute respiratory distress syndrome: Mechanistic insights and therapeutic perspectives (Review)

  • Authors:
    • Yue Zhang
    • Hongzhi He
    • Chufan Dong
    • Qing Guo
    • Jiuwen Tan
    • Yonggui Yang
    • Zhuangbo Guo
    • Rui Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Emergency Medicine, Guangzhou Red Cross Hospital (Guangzhou Red Cross Hospital of Jinan University), Guangzhou, Guangdong 510240, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 156
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    Published online on: April 8, 2026
       https://doi.org/10.3892/etm.2026.13151
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Abstract

Acute respiratory distress syndrome (ARDS) is a life‑threatening pulmonary disorder frequently encountered in intensive care units, characterized by diffuse alveolar damage, intense inflammatory infiltration and progressive fibrotic remodeling. Among the mechanisms driving fibrosis, the epithelial‑mesenchymal transition (EMT) has gained increasing recognition as a key contributor to the generation of fibroblasts and extracellular matrix deposition. Autophagy, a tightly regulated intracellular degradation and recycling process, serves a context‑dependent role in EMT regulation and lung injury. While basal autophagy supports pulmonary cellular homeostasis, dysregulated or excessive autophagy may exacerbate tissue injury and maladaptive repair. The literature has previously highlighted both classical macroautophagy and selective autophagy pathways, including mitophagy, endoplasmic reticulum‑selective autophagy and ferritinophagy, as modulators of EMT dynamics and fibrotic outcomes. However, the mechanistic associations between specific autophagy subtypes and EMT in ARDS remain poorly defined and occasionally contradictory. In the present review, current evidence on autophagy‑EMT crosstalk in ARDS is critically appraised, conceptual gaps and controversies are identified and further potential mechanistic frameworks and research priorities are summarized. Such investigation may help inform the rational targeting of autophagy pathways in future ARDS therapies. 
View Figures

Figure 1

Mechanistic overview of ARDS
progression. Schematic illustrates the major pathological events in
ARDS, organized into four interrelated stages surrounding a central
lung diagram. Stage 1: Alveolar-capillary barrier damage.
Structural disruption of the alveolar-capillary interface allows
leakage of plasma and proteins into alveoli (ARDS-specific). Stage
2: Recruitment of inflammatory cells and mediator release.
Neutrophils, macrophages and cytokines accumulate, amplifying local
inflammation (ARDS-specific). Stage 3: Increased vascular
permeability and pulmonary edema formation. Fluid extravasation
into alveolar and interstitial spaces (ARDS-specific). Stage 4:
Oxygenation impairment and hypoxemia. Impaired gas exchange results
in reduced oxygen saturation (ARDS-specific). Arrows indicate the
direction of pathological progression. Early fibroproliferative
responses, shown schematically, highlight the onset of tissue
remodeling, a hallmark of poor prognosis. ARDS, acute respiratory
distress syndrome.

Figure 2

Macroautophagy process and key
regulatory pathways. Diagram showing the sequential steps of
autophagy and their upstream molecular regulators. Autophagy
process: i) Initiation; ii) phagophore formation; iii)
autophagosome maturation; iv) autophagosome-lysosome fusion; v)
autolysosome; and vi) degradation and recycling (general
mechanism). Regulatory pathways: mTOR integrates upstream signals
from PI3K/AKT and MAPK/ERK (activators) and AMPK (inhibitor). ULK1
complex mediates phagophore nucleation downstream of mTOR. p53
modulates autophagy indirectly under stress conditions. Contextual
relevance: Moderate autophagy during early ARDS protects alveolar
epithelial and endothelial cells, maintaining barrier integrity
(ARDS-specific), whereas excessive or prolonged activation may
trigger autophagic cell death and fibrosis (partially extrapolated
from other models). Arrows indicate activation or inhibition. ARDS,
acute respiratory distress syndrome; ULK1, unc-51-like kinase 1;
AMPK, AMP-activated protein kinase.

Figure 3

Classification of EMT and relevance
to ARDS. Schematic depicting the conversion from epithelial to
mesenchymal phenotypes and three EMT subtypes. Type I EMT: Occurs
during embryogenesis and organ development. Epithelial cells
gradually acquire mesenchymal traits (extrapolated evidence). Type
II EMT: Associated with wound healing, tissue regeneration and
organ fibrosis. Closely resembles EMT observed in ARDS, driven by
profibrotic and inflammatory signaling, including TGF-β,
WNT/β-catenin and Notch pathways (ARDS-specific). Type III EMT:
Implicated in cancer invasion and metastasis (extrapolated
evidence). Arrows indicate phenotypic transitions. Dashed boxes
highlight ARDS-relevant Type II EMT. Schematic emphasizes the
context- and disease-specific nature of EMT in fibrotic lung
remodeling. EMT, epithelial-mesenchymal transition; ARDS, acute
respiratory distress syndrome.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang Y, He H, Dong C, Guo Q, Tan J, Yang Y, Guo Z and Zhang R: Autophagy‑epithelial‑mesenchymal transition crosstalk in acute respiratory distress syndrome: Mechanistic insights and therapeutic perspectives (Review). Exp Ther Med 31: 156, 2026.
APA
Zhang, Y., He, H., Dong, C., Guo, Q., Tan, J., Yang, Y. ... Zhang, R. (2026). Autophagy‑epithelial‑mesenchymal transition crosstalk in acute respiratory distress syndrome: Mechanistic insights and therapeutic perspectives (Review). Experimental and Therapeutic Medicine, 31, 156. https://doi.org/10.3892/etm.2026.13151
MLA
Zhang, Y., He, H., Dong, C., Guo, Q., Tan, J., Yang, Y., Guo, Z., Zhang, R."Autophagy‑epithelial‑mesenchymal transition crosstalk in acute respiratory distress syndrome: Mechanistic insights and therapeutic perspectives (Review)". Experimental and Therapeutic Medicine 31.6 (2026): 156.
Chicago
Zhang, Y., He, H., Dong, C., Guo, Q., Tan, J., Yang, Y., Guo, Z., Zhang, R."Autophagy‑epithelial‑mesenchymal transition crosstalk in acute respiratory distress syndrome: Mechanistic insights and therapeutic perspectives (Review)". Experimental and Therapeutic Medicine 31, no. 6 (2026): 156. https://doi.org/10.3892/etm.2026.13151
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang Y, He H, Dong C, Guo Q, Tan J, Yang Y, Guo Z and Zhang R: Autophagy‑epithelial‑mesenchymal transition crosstalk in acute respiratory distress syndrome: Mechanistic insights and therapeutic perspectives (Review). Exp Ther Med 31: 156, 2026.
APA
Zhang, Y., He, H., Dong, C., Guo, Q., Tan, J., Yang, Y. ... Zhang, R. (2026). Autophagy‑epithelial‑mesenchymal transition crosstalk in acute respiratory distress syndrome: Mechanistic insights and therapeutic perspectives (Review). Experimental and Therapeutic Medicine, 31, 156. https://doi.org/10.3892/etm.2026.13151
MLA
Zhang, Y., He, H., Dong, C., Guo, Q., Tan, J., Yang, Y., Guo, Z., Zhang, R."Autophagy‑epithelial‑mesenchymal transition crosstalk in acute respiratory distress syndrome: Mechanistic insights and therapeutic perspectives (Review)". Experimental and Therapeutic Medicine 31.6 (2026): 156.
Chicago
Zhang, Y., He, H., Dong, C., Guo, Q., Tan, J., Yang, Y., Guo, Z., Zhang, R."Autophagy‑epithelial‑mesenchymal transition crosstalk in acute respiratory distress syndrome: Mechanistic insights and therapeutic perspectives (Review)". Experimental and Therapeutic Medicine 31, no. 6 (2026): 156. https://doi.org/10.3892/etm.2026.13151
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