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Tumour derived exosomal DDAH1 promotes lung aging and metastasis

ABSTRACT: Aging is a multifactorial series of molecular alterations that leads to gradual deterioration of tissue function and increased vulnerability to disease and death. Primary tumor communicates with host organs partially through extracellular vesicles. However, the mechanistic drivers of lung aging in the context of cancer remain unclear. Here, we identify cancer cell-secreted dimethylarginine dimethylaminohydrolase-1 (DDAH1) protein induces citrulline accumulation in lung tissue and promotes lung aging. Mechanistically, single cell sequencing and genetic knockout mice evidence that elevation of citrulline availability inhibits peptidylarginine deiminase 4 (PAD4)-mediated transforming growth factor-β (TGF-β1) citrullination, thereby inducing the TGF-β1/Smad3 signaling pathway in lung fibroblasts. Notably, vacuolar protein sorting 35 (VPS35) assists the package of DDAH1 into late endosome. Employing DDAH1 inhibitor PD 404182 treatment reduces lung fibrosis and alleviates lung aging. Conclusively, our finding reveals cancer cell-secreted DDAH1 protein contributes to citrulline accumulation to promote lung aging, shedding light on future applications for the treatment and diagnosis of tumor by clearance of senescent lung fibroblasts.

ORGANISM(S): Homo Sapiens

SUBMITTER: Wei Yan

PROVIDER: PXD061162 | iProX | Thu Oct 16 00:00:00 BST 2025

REPOSITORIES: iProX

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