ArticleClinical and translational medicine2023
Inflammasome activation and metabolic remodelling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1.
Article in Clinical and translational medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 12 papers.
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12 citing papers in PubMed, 24 citations in OpenAlex.
- Metabolic reprogramming in fibrosis-related diseases: underlying mechanisms and therapeutics.Molecular biomedicine · 2026Review
- NEDD4L knockdown enhances synovial fibroblast migration, invasion, and inflammatory factor secretion via Wnt/β-Catenin signaling activation.Clinical rheumatology · 2026Article
- Tissue Fibrosis Decoded via Cellular Senescence: Mechanisms, Treatments, and Emerging Technologies.Aging and disease · 2025Review
- The E3 Ligase NEDD4L Prevents Colorectal Cancer Liver Metastasis via Degradation of PRMT5 to Inhibit the AKT/mTOR Signaling Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Integrins and pulmonary fibrosis: Pathogenic roles and therapeutic opportunities.Biomolecules & biomedicine · 2025Review
- Tumor exosomal circPTBP3 drives gastric cancer peritoneal metastasis via mesothelial-mesenchymal transition.Cell death & disease · 2025Article
- Fibroblasts-specific p16Clinical and translational medicine · 2025Article
- p16Journal of cardiovascular translational research · 2025Article
- p16INK4a Deletion Alleviated Obesity-Associated Kidney Fibrosis by Regulating Metabolic Reprogramming and the Inflammasome Pathway.Journal of cellular and molecular medicine · 2025Article
- SGK1 aggravates idiopathic pulmonary fibrosis by triggering H3k27ac-mediated macrophage reprogramming and disturbing immune homeostasis.International journal of biological sciences · 2024Article
- Muscone ameliorates myocardial ischemia‒reperfusion injury by promoting myocardial glycolysis.Heliyon · 2023Article
- Inflammasome activation and metabolic remodelling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1.Clinical and translational medicine · 2023Article
Corrections and comments
- Erratum issued
Authors and funding
15 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundChronic changes caused by a high-fat diet (HFD) may be associated with weakened lung function in obese patients. However, few studies have focused on the role of senescent cells in HFD-induced 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-term HFD-induced senescence-associated pulmonary fibrosis (SAPF) and (iii) p16 deletion or clearance of aging cells ameliorates HFD-induced SAPF through inactivation of the inflammasome and metabolic remodelling.
methodsTwelve-month old male mice of p16
resultsWe found that long-term HFD promoted the expression of p16 and the increase of senescent cells in the lung. P16 knockout or ABT263 treatment alleviated pulmonary fibrosis, the increase of senescent cells and senescence-associated secretory phenotype (SASP) in HFD-fed mice, as well as in P&O-treated A549 and IMR-90 cells. RNA sequencing and bioinformatics analyses revealed that p16 knockout inhibited activation of the integrin-inflammasome pathway and cellular glycolysis. Mass spectrometry, co-immunoprecipitation and GST pull-down assays demonstrated that p16 bound to the N-terminal of SGK1, thereby interfering with the interaction between the E3 ubiquitin ligase NEDD4L and SGK1, and subsequently inhibiting K48-polyubiquitin-dependent degradation of SGK1 mediated by the NEDD4L-Ubch5 complex. EMD638683 was found to alleviate HFD-induced pulmonary fibrosis and activation of the integrin-inflammasome pathway.
conclusionP16 accumulation promoted activation of integrin- inflammasome pathway and cell glycolysis by binding to the N- terminal of SGK1, intefering with the interaction between the E3 ubiquitin ligase NEDD4L and SGK1, thereby inhibiting K48- polyubiquitin- dependent degradation of SGK1 mediated by the NEDD4L-Ubch5 complex. ABT263 or EMD638683 could be used as potential drugs to treat pulmonary fibrosis in obese patients.
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