Tier 3 — preclinical

Nuclear SIRT6 depletion activates LINE1-cGAS-STING pathway to induce PASMCs senescence in hypoxic pulmonary hypertension

Meng Wang, Meiling Zhang, Jian Chen, Yan Wang, Junming Zhang, Yuwen Dai, Chenfei Zhao, Yukun Gan, Limin Liu, Zhichao Li
Cellular Signalling 2026 139:112351

Bibliography

PubMed
PMID 41490817
DOI
10.1016/j.cellsig.2025.112351
Competing interests
Authors reported no known competing financial interests or personal relationships; the PubMed record notes support/resources from the National Natural Science Foundation of China.

Study snapshot

DesignMechanistic cell and rat pulmonary-hypertension study with pharmacological SIRT6 activation/inhibition.
ModelHypoxic pulmonary artery smooth muscle cells and monocrotaline-induced pulmonary hypertension models.
SampleMultiple cell and animal experiments; exact group sizes not stated in the indexed abstract.
InterventionUBCS039 SIRT6 activation; OSS-128167 SIRT6 inhibition; LINE1 cDNA reduction experiments.
DurationModel-specific experimental durations.
EndpointsNuclear SIRT6; LINE1 activity; cGAS-STING signaling; p16 and beta-galactosidase senescence markers; Inflammatory response; PASMC proliferation

What the study showed, in plain terms

Hypoxia reduced nuclear SIRT6 in pulmonary artery smooth-muscle cells, allowing LINE1 activity and cGAS-STING inflammatory signaling to rise. Activating SIRT6 with UBCS039 suppressed this pathway, while inhibiting SIRT6 reproduced the senescent phenotype.

Key findings

The study provides a direct disease-model extension of the SIRT6-LINE1-cGAS-STING aging mechanism: SIRT6 activation reduced LINE1 signaling and cellular senescence in pulmonary-hypertension models.

What this study can and cannot tell us

This is preclinical disease-model evidence. It does not show that a consumer SIRT6 supplement prevents or treats pulmonary hypertension in humans.

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Last verified

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability