Cryptochrome Loss Drives COPD-like Lung Pathology through Disrupted Alveolar Epithelial Proliferation and Immune Homeostasis.

Jun 4, 2026bioRxiv : the preprint server for biology

Loss of Cryptochrome May Cause COPD-Like Lung Damage by Disrupting Lung Cell Growth and Immune Balance

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Abstract

Double knockout mice lacking Cryptochrome 1 and 2 exhibit spontaneous emphysema-like pathology.

These mice show airspace enlargement, increased lung compliance, and inflammatory cell infiltration without environmental insults.
Deficient alveolar epithelial cells have reduced ability to proliferate and display a gene signature resembling human COPD lungs.
Elevated responsiveness to LPS is observed in macrophages lacking Cryptochrome 1 and 2.
Bone marrow transplantation indicates that epithelial cells play a critical role in maintaining alveolar integrity.
Treatment with Nobiletin reduces NF-κB activation, improving lung inflammation and structural damage in double knockout mice.

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Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by alveolar destruction, impaired epithelial regeneration and chronic inflammation. While circadian disruption has been linked to COPD pathogenesis, the cellular mechanisms remain unclear. Here, we identify the core clock components Cryptochrome 1 and 2 () as essential regulators of alveolar epithelial cell proliferation and pulmonary immune homeostasis.double knockout (dKO) mice exhibit spontaneous emphysema-like pathology, including airspace enlargement, increased lung compliance, and inflammatory cell infiltration without environmental insults. Mechanistically,-deficient alveolar epithelial cells display reduced proliferative capacity, and transcriptomic profiling revealed a pronounced shift toward a more proximal airway-like phenotype. Notably, these cells share a gene signature with human COPD lungs in pathways involving immune regulation. Furthermore,-deficient macrophages show elevated responsiveness to LPS. Bone marrow (BM) transplantation revealed that mice receivingdKO BM suffer from enhanced lung inflammation without airspace enlargement, supporting a critical role of epithelialin maintaining alveolar integrity. Importantly, treatment with Nobiletin, a circadian rhythm-modulating compound, mitigates NF-κB activation and ameliorates lung inflammation and structural damage indKO mice. These findings establish CRY1/2 as critical circadian regulators of epithelial cell proliferation and immune homeostasis, and highlight the therapeutic potential of targeting circadian pathways in COPD. Cry1/2Cry1/2Cry1/2Cry1/2Cry1/2Cry1/2Cry1/2

Cryptochrome Loss Drives COPD-like Lung Pathology through Disrupted Alveolar Epithelial Proliferation and Immune Homeostasis.

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