PPARG/SPP1/CD44 signaling pathway in alveolar macrophages: Mechanisms of lipid dysregulation and therapeutic targets in idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease. It is characterized by inflammation and fibrosis in the lung parenchyma and interstitium. Given its poor prognosis and limited treatment options, understanding the underlying molecular mechanisms is crucial....
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Elsevier
2025-01-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844025000076 |
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| author | Ganggang Li Yuwei Zhang Huanyu Jiang Xuanyu Wu Yanwei Hao Yuchen Su Yutong Zou Wenjia Xian Fei Wang Quanyu Du |
| author_facet | Ganggang Li Yuwei Zhang Huanyu Jiang Xuanyu Wu Yanwei Hao Yuchen Su Yutong Zou Wenjia Xian Fei Wang Quanyu Du |
| author_sort | Ganggang Li |
| collection | DOAJ |
| description | Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease. It is characterized by inflammation and fibrosis in the lung parenchyma and interstitium. Given its poor prognosis and limited treatment options, understanding the underlying molecular mechanisms is crucial. Recent evidence suggests that lipid metabolism plays a pivotal role in IPF pathogenesis, however, the precise mechanisms remain poorly understood. To address this, we analyzed 12 bulk RNA-seq and 2 single-cell RNA-seq datasets from the GEO database using machine learning approaches. As a result, we identified four key lipid-related genes—PPARG, SPP1, CASP3, and PECAM1—that are expressed across various cell types. Specifically, in alveolar macrophages (AMs), we observed that PPARG was significantly downregulated, while SPP1 was highly expressed. Importantly, PPARG serves as a transcriptional regulator of SPP1, which in turn mediates intercellular signaling via CD44. Based on these findings, we propose a novel PPARG/SPP1/CD44 signaling pathway in AMs, which modulates lipid metabolism and likely contributes to the progression of fibrosis in IPF. Moreover, network pharmacology analysis identified several herbal compounds that target PPARG, offering potential therapeutic opportunities. In conclusion, these findings highlight the critical role of lipid metabolism in IPF and present novel molecular targets for the development of future therapeutic strategies. |
| format | Article |
| id | doaj-art-874741b2326c412ca0d44c480e82eb9c |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-874741b2326c412ca0d44c480e82eb9c2025-01-17T04:51:47ZengElsevierHeliyon2405-84402025-01-01111e41628PPARG/SPP1/CD44 signaling pathway in alveolar macrophages: Mechanisms of lipid dysregulation and therapeutic targets in idiopathic pulmonary fibrosisGanggang Li0Yuwei Zhang1Huanyu Jiang2Xuanyu Wu3Yanwei Hao4Yuchen Su5Yutong Zou6Wenjia Xian7Fei Wang8Quanyu Du9Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, ChinaDepartment of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, ChinaSchool of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 611130, ChinaDepartment of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, ChinaDepartment of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, ChinaDepartment of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, ChinaDepartment of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, ChinaDepartment of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, ChinaDepartment of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, China; Corresponding author.Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, Sichuan, 610072, China; Corresponding author. Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, 610072, China.Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease. It is characterized by inflammation and fibrosis in the lung parenchyma and interstitium. Given its poor prognosis and limited treatment options, understanding the underlying molecular mechanisms is crucial. Recent evidence suggests that lipid metabolism plays a pivotal role in IPF pathogenesis, however, the precise mechanisms remain poorly understood. To address this, we analyzed 12 bulk RNA-seq and 2 single-cell RNA-seq datasets from the GEO database using machine learning approaches. As a result, we identified four key lipid-related genes—PPARG, SPP1, CASP3, and PECAM1—that are expressed across various cell types. Specifically, in alveolar macrophages (AMs), we observed that PPARG was significantly downregulated, while SPP1 was highly expressed. Importantly, PPARG serves as a transcriptional regulator of SPP1, which in turn mediates intercellular signaling via CD44. Based on these findings, we propose a novel PPARG/SPP1/CD44 signaling pathway in AMs, which modulates lipid metabolism and likely contributes to the progression of fibrosis in IPF. Moreover, network pharmacology analysis identified several herbal compounds that target PPARG, offering potential therapeutic opportunities. In conclusion, these findings highlight the critical role of lipid metabolism in IPF and present novel molecular targets for the development of future therapeutic strategies.http://www.sciencedirect.com/science/article/pii/S2405844025000076Idiopathic pulmonary fibrosisLipid metabolismAlveolar macrophagePPARGSPP1CD44 |
| spellingShingle | Ganggang Li Yuwei Zhang Huanyu Jiang Xuanyu Wu Yanwei Hao Yuchen Su Yutong Zou Wenjia Xian Fei Wang Quanyu Du PPARG/SPP1/CD44 signaling pathway in alveolar macrophages: Mechanisms of lipid dysregulation and therapeutic targets in idiopathic pulmonary fibrosis Heliyon Idiopathic pulmonary fibrosis Lipid metabolism Alveolar macrophage PPARG SPP1 CD44 |
| title | PPARG/SPP1/CD44 signaling pathway in alveolar macrophages: Mechanisms of lipid dysregulation and therapeutic targets in idiopathic pulmonary fibrosis |
| title_full | PPARG/SPP1/CD44 signaling pathway in alveolar macrophages: Mechanisms of lipid dysregulation and therapeutic targets in idiopathic pulmonary fibrosis |
| title_fullStr | PPARG/SPP1/CD44 signaling pathway in alveolar macrophages: Mechanisms of lipid dysregulation and therapeutic targets in idiopathic pulmonary fibrosis |
| title_full_unstemmed | PPARG/SPP1/CD44 signaling pathway in alveolar macrophages: Mechanisms of lipid dysregulation and therapeutic targets in idiopathic pulmonary fibrosis |
| title_short | PPARG/SPP1/CD44 signaling pathway in alveolar macrophages: Mechanisms of lipid dysregulation and therapeutic targets in idiopathic pulmonary fibrosis |
| title_sort | pparg spp1 cd44 signaling pathway in alveolar macrophages mechanisms of lipid dysregulation and therapeutic targets in idiopathic pulmonary fibrosis |
| topic | Idiopathic pulmonary fibrosis Lipid metabolism Alveolar macrophage PPARG SPP1 CD44 |
| url | http://www.sciencedirect.com/science/article/pii/S2405844025000076 |
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