Saroglitazar Ameliorates Pulmonary Fibrosis Progression in Mice by Suppressing NF-κB Activation and Attenuating Macrophage M1 Polarization
<i>Background and Objectives</i>: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited therapeutic options. Current therapies (pirfenidone, nintedanib) exhibit modest efficacy and significant side effects, underscoring the need for novel s...
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MDPI AG
2025-06-01
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| author | Yawen Zhang Jiaquan Lin Xiaodong Han Xiang Chen |
| author_facet | Yawen Zhang Jiaquan Lin Xiaodong Han Xiang Chen |
| author_sort | Yawen Zhang |
| collection | DOAJ |
| description | <i>Background and Objectives</i>: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited therapeutic options. Current therapies (pirfenidone, nintedanib) exhibit modest efficacy and significant side effects, underscoring the need for novel strategies targeting early pathogenic drivers. Saroglitazar (SGZ), a dual PPARα/γ agonist with anti-inflammatory properties approved for diabetic dyslipidemia, has not been explored for IPF. We aimed to investigate SGZ’s therapeutic potential in pulmonary fibrosis and elucidate its mechanisms of action. <i>Materials and Methods</i>: Using a bleomycin (BLM)-induced murine pulmonary fibrosis model, we administered SGZ therapeutically. A histopathological assessment (H&E, Masson’s trichrome, collagen I immunofluorescence), Western blotting, and qRT-PCR analyzed the fibrosis progression and inflammatory markers. Flow cytometry evaluated the macrophage polarization. In vitro studies used RAW264.7 macrophages stimulated with BLM/LPS and MRC-5 fibroblast co-cultures. The NF-κB/NLRP3 pathway activation was assessed through protein and gene expression. <i>Results</i>: SGZ significantly attenuated BLM-induced histopathological hallmarks, including alveolar wall thickening, collagen deposition, and inflammatory infiltration. Fibrotic markers (OPN, α-SMA) and pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) were downregulated in the SGZ-treated mice. Mechanistically, SGZ suppressed the M1 macrophage polarization (reduced CD86<sup>+</sup> populations) and inhibited the NF-κB/NLRP3 pathway activation in the alveolar macrophages. In the RAW264.7 cells, SGZ decreased the NLRP3 inflammasome components (ASC, cleaved IL-1β) and cytokine secretion. Co-cultures demonstrated that the SGZ-treated macrophage supernatants suppressed the fibroblast activation (α-SMA, collagen I) in MRC-5 cells. <i>Conclusions</i>: SGZ attenuates pulmonary fibrosis by suppressing macrophage-driven inflammation via NF-κB/NLRP3 inhibition and disrupting the macrophage–fibroblast crosstalk. These findings nominate SGZ as a promising candidate for preclinical optimization and future clinical evaluation in IPF. |
| format | Article |
| id | doaj-art-20b480e1db524082bd08194057fdeba4 |
| institution | DOAJ |
| issn | 1010-660X 1648-9144 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Medicina |
| spelling | doaj-art-20b480e1db524082bd08194057fdeba42025-08-20T02:47:07ZengMDPI AGMedicina1010-660X1648-91442025-06-01617115710.3390/medicina61071157Saroglitazar Ameliorates Pulmonary Fibrosis Progression in Mice by Suppressing NF-κB Activation and Attenuating Macrophage M1 PolarizationYawen Zhang0Jiaquan Lin1Xiaodong Han2Xiang Chen3State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing 210093, ChinaJiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, ChinaState Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing 210093, ChinaState Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing 210093, China<i>Background and Objectives</i>: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited therapeutic options. Current therapies (pirfenidone, nintedanib) exhibit modest efficacy and significant side effects, underscoring the need for novel strategies targeting early pathogenic drivers. Saroglitazar (SGZ), a dual PPARα/γ agonist with anti-inflammatory properties approved for diabetic dyslipidemia, has not been explored for IPF. We aimed to investigate SGZ’s therapeutic potential in pulmonary fibrosis and elucidate its mechanisms of action. <i>Materials and Methods</i>: Using a bleomycin (BLM)-induced murine pulmonary fibrosis model, we administered SGZ therapeutically. A histopathological assessment (H&E, Masson’s trichrome, collagen I immunofluorescence), Western blotting, and qRT-PCR analyzed the fibrosis progression and inflammatory markers. Flow cytometry evaluated the macrophage polarization. In vitro studies used RAW264.7 macrophages stimulated with BLM/LPS and MRC-5 fibroblast co-cultures. The NF-κB/NLRP3 pathway activation was assessed through protein and gene expression. <i>Results</i>: SGZ significantly attenuated BLM-induced histopathological hallmarks, including alveolar wall thickening, collagen deposition, and inflammatory infiltration. Fibrotic markers (OPN, α-SMA) and pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) were downregulated in the SGZ-treated mice. Mechanistically, SGZ suppressed the M1 macrophage polarization (reduced CD86<sup>+</sup> populations) and inhibited the NF-κB/NLRP3 pathway activation in the alveolar macrophages. In the RAW264.7 cells, SGZ decreased the NLRP3 inflammasome components (ASC, cleaved IL-1β) and cytokine secretion. Co-cultures demonstrated that the SGZ-treated macrophage supernatants suppressed the fibroblast activation (α-SMA, collagen I) in MRC-5 cells. <i>Conclusions</i>: SGZ attenuates pulmonary fibrosis by suppressing macrophage-driven inflammation via NF-κB/NLRP3 inhibition and disrupting the macrophage–fibroblast crosstalk. These findings nominate SGZ as a promising candidate for preclinical optimization and future clinical evaluation in IPF.https://www.mdpi.com/1648-9144/61/7/1157pulmonary fibrosisinflammationsaroglitazarM1 macrophage polarizationNF-κB pathway |
| spellingShingle | Yawen Zhang Jiaquan Lin Xiaodong Han Xiang Chen Saroglitazar Ameliorates Pulmonary Fibrosis Progression in Mice by Suppressing NF-κB Activation and Attenuating Macrophage M1 Polarization Medicina pulmonary fibrosis inflammation saroglitazar M1 macrophage polarization NF-κB pathway |
| title | Saroglitazar Ameliorates Pulmonary Fibrosis Progression in Mice by Suppressing NF-κB Activation and Attenuating Macrophage M1 Polarization |
| title_full | Saroglitazar Ameliorates Pulmonary Fibrosis Progression in Mice by Suppressing NF-κB Activation and Attenuating Macrophage M1 Polarization |
| title_fullStr | Saroglitazar Ameliorates Pulmonary Fibrosis Progression in Mice by Suppressing NF-κB Activation and Attenuating Macrophage M1 Polarization |
| title_full_unstemmed | Saroglitazar Ameliorates Pulmonary Fibrosis Progression in Mice by Suppressing NF-κB Activation and Attenuating Macrophage M1 Polarization |
| title_short | Saroglitazar Ameliorates Pulmonary Fibrosis Progression in Mice by Suppressing NF-κB Activation and Attenuating Macrophage M1 Polarization |
| title_sort | saroglitazar ameliorates pulmonary fibrosis progression in mice by suppressing nf κb activation and attenuating macrophage m1 polarization |
| topic | pulmonary fibrosis inflammation saroglitazar M1 macrophage polarization NF-κB pathway |
| url | https://www.mdpi.com/1648-9144/61/7/1157 |
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