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

Hypoxic pulmonary hypertension (HPH) is a complex vascular disease that is difficult to reverse in its advanced stages and has a poor prognosis. Senescent pulmonary artery smooth muscle cells (PASMCs) had been shown to secrete senescence-associated secretory phenotype (SASP) mediators in HPH, including the pro-inflammatory factors IL-6 and IL-8, which up-regulate the inflammatory response, but the upstream regulatory mechanisms linking hypoxia to senescence remain elusive. SIRT6 regulates retrotransposon silencing, and LINE1 activation triggers cGAS-STING-mediated inflammation, yet their crosstalk in HPH is unreported. Our results show that hypoxia reduced nuclear SIRT6 abundance in PASMCs, which was associated with increased LINE1 activity, cGAS-STING pathway activation, and increased senescence markers (P16^INK4A, β-galactosidase). SIRT6 activation (UBCS039) suppressed LINE1-cGAS-STING signaling and alleviated senescence, while SIRT6 inhibition (OSS-128167) recapitulated the hypoxic phenotype. Similar changes were observed in MCT-induced PH models. In addition, clearing the accumulation of LINE1 cDNA in the cytoplasm can inhibit the senescence of PASMCs, thereby reducing the inflammatory response and proliferation of PASMCs. Our findings identify the nuclear SIRT6-LINE1-cGAS-STING axis as a novel regulator of PASMCs senescence in HPH, providing a potential therapeutic target.

Cellular senescence; Hypoxic pulmonary hypertension; LINE1; Pulmonary artery smooth muscle cells; SIRT6.