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Elucidation of mechanisms underlying the therapeutic effects of cordycepin on pulmonary hypertension, with a focus on cell senescence and gut microbiota.

Gaopeng Li,Zhixin Zhao,M. Machitani,Ryou Ishikawa,Kaori Ishikawa,Naoya Yokota,Reiji Haba,Kazufumi Nakamura,Zhihong Sun,L. Kurahara,K. Hirano

Published 2026 in Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

ABSTRACT

INTRODUCTION Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by excessive pulmonary vascular remodeling and aberrant proliferation of pulmonary artery smooth muscle cells (PASMCs). Emerging evidence suggests that gut microbiota dysbiosis contributes to PH development. Cordycepin, a natural adenosine analogue derived from Cordyceps militaris, has demonstrated antiproliferative and microbiota-modulating properties; however, its mechanism of action in PH remains unclear. OBJECTIVE Elucidate the mechanisms underlying the therapeutic effects of cordycepin on PH, focusing on cellular senescence and gut microbiota. METHODS The effects of cordycepin on PH pathology were investigated by transcriptome analysis of PASMCs from patients, and metagenomic analysis of rodent PH models. Cellular senescence was analyzed in lung tissue from p16Ink4a-CreERT2 reporter mice and in rat bone marrow-derived macrophages (BMDMs). RESULTS RNA sequencing analysis revealed activation of p53 signaling by cordycepin in PASMCs. Cordycepin suppressed CDK1 expression and TERT phosphorylation at threonine 249. It ameliorated vascular and cardiac remodeling in PH rat and mouse models. Cordycepin induced M1-like macrophage senescence in p16 Ink4a reporter mice lungs and rat BMDMs. Cordycepin significantly reshaped the gut microbiota, increasing beneficial genera (e.g. Alistipes and Acetatifactor) and reducing proinflammatory taxa (e.g., Ruminococcus), with modulating key metabolic pathways, including short-chain fatty acid, tryptophan, and vitamin K2 metabolism. CONCLUSION Cordycepin exerts multi-target therapeutic effects in PH by inhibiting PASMC proliferation via the p53-CDK1/pTERT axis, modulating gut microbiota-linked immunometabolism and induces proinflammatory macrophage senescence. These findings support cordycepin as a promising candidate for PH therapies targeting the vascular, immune, and gut-lung axes.

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