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However, few studies have focused on the role of senescent cells in HFD\u2010induced pulmonary fibrosis. This study aimed to determine whether (i) obesity causes the accumulation of aging cells in the lungs, (ii) p16 accumulation in aging epithelial cells or fibroblasts exacerbates long\u2010term HFD\u2010induced senescence\u2010associated pulmonary fibrosis (SAPF) and (iii) <jats:italic>p16<\/jats:italic> deletion or clearance of aging cells ameliorates HFD\u2010induced SAPF through inactivation of the inflammasome and metabolic remodelling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Twelve\u2010month old male mice of <jats:italic>p16<jats:sup>INK4a<\/jats:sup><\/jats:italic> (hereafter p16) knockout (<jats:italic>p16<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) and wild\u2010type (WT), <jats:italic>ApoE<\/jats:italic> knockout (<jats:italic>ApoE<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic>) and <jats:italic>ApoE<jats:sup>\u2212\/\u2212<\/jats:sup>p16<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> were fed a HFD to induce obesity, and the effects of treatment with the senolytic drug ABT263 or the SGK1 specific inhibitor EMD638683 on fibrosis, inflammaging, gene expression, integrin\u2010inflammasome signalling and metabolism were examined. A549 and IMR\u201090 cells were transduced with <jats:italic>p16<\/jats:italic>\u2010overexpressing adenovirus, and treated with palmitic and oleic acids (P&amp;O) to induce steatosis in vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found that long\u2010term HFD promoted the expression of p16 and the increase of senescent cells in the lung. <jats:italic>P16<\/jats:italic> knockout or ABT263 treatment alleviated pulmonary fibrosis, the increase of senescent cells and senescence\u2010associated secretory phenotype (SASP) in HFD\u2010fed mice, as well as in P&amp;O\u2010treated A549 and IMR\u201090 cells. RNA sequencing and bioinformatics analyses revealed that <jats:italic>p16<\/jats:italic> knockout inhibited activation of the integrin\u2010inflammasome pathway and cellular glycolysis. Mass spectrometry, co\u2010immunoprecipitation and GST pull\u2010down assays demonstrated that p16 bound to the <jats:italic>N<\/jats:italic>\u2010terminal of SGK1, thereby interfering with the interaction between the E3 ubiquitin ligase NEDD4L and SGK1, and subsequently inhibiting K48\u2010polyubiquitin\u2010dependent degradation of SGK1 mediated by the NEDD4L\u2013Ubch5 complex. EMD638683 was found to alleviate HFD\u2010induced pulmonary fibrosis and activation of the integrin\u2010inflammasome pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>P16 accumulation promoted activation of integrin\u2013 inflammasome pathway and cell glycolysis by binding to the N\u2013 terminal of SGK1, intefering with the interaction between the E3 ubiquitin ligase NEDD4L and SGK1, thereby inhibiting K48\u2013 polyubiquitin\u2013 dependent degradation of SGK1 mediated by the NEDD4L\u2013Ubch5 complex. ABT263 or EMD638683 could be used as potential drugs to treat pulmonary fibrosis in obese patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.1308","type":"journal-article","created":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T13:06:26Z","timestamp":1687611986000},"source":"Crossref","is-referenced-by-count":23,"title":["Inflammasome activation and metabolic remodelling in p16\u2010positive aging cells aggravates high\u2010fat diet\u2010induced lung fibrosis by inhibiting NEDD4L\u2010mediated K48\u2010polyubiquitin\u2010dependent degradation of SGK1"],"prefix":"10.1002","volume":"13","author":[{"given":"Xin","family":"Gu","sequence":"first","affiliation":[{"name":"Department of Cardiology Affiliated Hospital of Jiangnan University Wuxi Jiangsu P. R. 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