Rutin interferes with hnRNP L phase separation and modulates the PKM2–lactate–H3K9la axis in pulmonary fibrosis
- 1School of Pharmacy, Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medical and Pharmaceutical University
- 2Department of Respiratory and Critical Care Medicine, Shandong Medical and Pharmaceutical University Hospital, Shandong Medical and Pharmaceutical University
Abstract
Background: Pulmonary fibrosis is a chronic and progressive lung disease with limited treatment options; it is urgent to develop new drugs.
Purpose: This study investigated the anti-pulmonary fibrosis effects and mechanism of rutin, and sought to provide a potential lead compound for further development of anti-pulmonary fibrosis agents.
Methods: The anti-pulmonary fibrosis effect of rutin was assessed using Cell Counting Kit-8 (CCK-8), real-time cell proliferation analysis and scratch wound healing assay in Transforming Growth Factor-β1(TGF-β1)-stimulated Medical Research Council cell strain-5 (MRC-5) cells, along with lung function tests, MicroCT imaging, Hematoxylin and Eosin (H&E) and Masson staining in mice with induced pulmonary fibrosis. The mechanism of rutin was explored through molecular docking, the surface plasmon resonance assay, the cell thermal shift assay (CETSA), droplet formation observation, fluorescence recovery after photobleaching, transcriptome sequencing, Enzyme Linked Immunosorbent Assay (ELISA), Co-immunoprecipitation (Co-IP) and Chromatin Immunoprecipitation-Polymerase Chain Reaction (ChIP-PCR).
Results: Rutin inhibited fibroblast-to-myofibroblast differentiation, myofibroblast proliferation and migration, and extracellular matrix deposition. Moreover, rutin effectively improved lung function, including forced vital capacity, dynamic lung compliance and total lung capacity. Additionally, rutin markedly alleviated fibrotic features, such as honeycomb lung reduction, preserved alveolar structure and thinned alveolar walls. Mechanistically, our data support a model in which rutin may interfere with hnRNP L phase separation, and this interference is associated with reduced PKM2 generation, decreased lactate production and subsequent loss of H3K9la. The reduced H3K9la, in turn, correlated with suppressed PKM2 transcription, suggesting a self-limiting regulatory circuit.
Conclusion: Our findings suggest that rutin may interfere with the regulatory interplay involving hnRNP L phase separation, PKM2 alternative splicing, lactate, and H3K9la, which is associated with the attenuation of pulmonary fibrosis. While these data reveal a potential mechanistic framework, definitive causality at each step of this regulatory axis remains to be established. Further studies are warranted to validate this model and to optimize the bioavailability of rutin for therapeutic application.
Related
- Lactate-associated fibroblast–macrophage signaling in idiopathic pulmonary fibrosis: evidence boundaries and immunopharmacological opportunities
- The lactate dehydrogenase-to-albumin ratio is independently associated with moderate-to-severe tubulointerstitial fibrosis in patients with IgA nephropathy.
- Inhibition of lactate-histone lactylation mediated cardiomyocyte-fibroblast communication mitigates cardiac fibrosis in cardiomyopathy models with Hippo pathway activation.
- Remote ischemic conditioning mitigates diesel exhaust-induced pulmonary fibrosis by alleviating pulmonary inflammation and fibrogenesis
- Absolute and lung volume-normalized deep learning-derived pulmonary vascular measures in idiopathic pulmonary fibrosis: distinct clinical associations and the role of lung volume in prognosis
BibTeX
@article{luan2026rutin,
title = {{Rutin interferes with hnRNP L phase separation and modulates the PKM2–lactate–H3K9la axis in pulmonary fibrosis}},
author = {Jianlin Luan and Yujie Wang and Mengqi Jiang and Haitong Zhang and Changjun Lv and Jinjin Zhang and Xiaodong Song},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1787570},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1787570/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Rutin interferes with hnRNP L phase separation and modulates the PKM2–lactate–H3K9la axis in pulmonary fibrosis
AU - Jianlin Luan
AU - Yujie Wang
AU - Mengqi Jiang
AU - Haitong Zhang
AU - Changjun Lv
AU - Jinjin Zhang
AU - Xiaodong Song
PY - 2026
DA - 2026/10/16
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1787570
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1787570/full
AB - Background: Pulmonary fibrosis is a chronic and progressive lung disease with limited treatment options; it is urgent to develop new drugs. Purpose: This study investigated the anti-pulmonary fibrosis effects and mechanism of rutin, and sought to provide a potential lead compound for further development of anti-pulmonary fibrosis agents. Methods: The anti-pulmonary fibrosis effect of rutin was assessed using Cell Counting Kit-8 (CCK-8), real-time cell proliferation analysis and scratch wound healing assay in Transforming Growth Factor-β1(TGF-β1)-stimulated Medical Research Council cell strain-5 (MRC-5) cells, along with lung function tests, MicroCT imaging, Hematoxylin and Eosin (H&E) and Masson staining in mice with induced pulmonary fibrosis. The mechanism of rutin was explored through molecular docking, the surface plasmon resonance assay, the cell thermal shift assay (CETSA), droplet formation observation, fluorescence recovery after photobleaching, transcriptome sequencing, Enzyme Linked Immunosorbent Assay (ELISA), Co-immunoprecipitation (Co-IP) and Chromatin Immunoprecipitation-Polymerase Chain Reaction (ChIP-PCR). Results: Rutin inhibited fibroblast-to-myofibroblast differentiation, myofibroblast proliferation and migration, and extracellular matrix deposition. Moreover, rutin effectively improved lung function, including forced vital capacity, dynamic lung compliance and total lung capacity. Additionally, rutin markedly alleviated fibrotic features, such as honeycomb lung reduction, preserved alveolar structure and thinned alveolar walls. Mechanistically, our data support a model in which rutin may interfere with hnRNP L phase separation, and this interference is associated with reduced PKM2 generation, decreased lactate production and subsequent loss of H3K9la. The reduced H3K9la, in turn, correlated with suppressed PKM2 transcription, suggesting a self-limiting regulatory circuit. Conclusion: Our findings suggest that rutin may interfere with the regulatory interplay involving hnRNP L phase separation, PKM2 alternative splicing, lactate, and H3K9la, which is associated with the attenuation of pulmonary fibrosis. While these data reveal a potential mechanistic framework, definitive causality at each step of this regulatory axis remains to be established. Further studies are warranted to validate this model and to optimize the bioavailability of rutin for therapeutic application.
SN - 1663-9812
ER -