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Limited efficacies of the available drugs drive researchers to seek for new therapies. Saroglitazar (Saro), a full (PPAR \u03b1\/\u03b3) agonist, is devoid of known PPAR-mediated adverse effects. Breast milk mesenchymal stem cells (BrMSCs) are contemplated to be the ideal cell type harboring differentiation\/anti-inflammatory\/immunosuppressive properties. Accordingly, our aims were to investigate the potential roles of Saro and\/or BrMSCs in PF and to spot their underlying protective mechanisms. In this study, PF was induced by bleomycin (BLM) via intratracheal instillation. Treatment started 14 days later. Animals were treated with oral saroglitazar (3 mg\/kg daily) or intraperitoneal single BrMSCs injection (0.5 ml phosphate buffer saline (PBS) containing 2\u2009\u00d7\u200910<jats:sup>7<\/jats:sup> cells) or their combination with same previous doses. At the work end, 24 h following the 6 weeks of treatment period, the levels of oxidative (MDA, SOD), inflammatory (IL-1\u00df, IL-10), and profibrotic markers (TGF-\u00df, \u03b1SMA) were assessed. The autophagy-related genes (LC3, Beclin) and the expression of PPAR-\u03b1\/\u03b3 and SMAD-3\/7 were evaluated. Furthermore, immunohistochemical and histological work were evaluated. Our study revealed marked lung injury influenced by BLM with severe oxidative\/inflammatory\/fibrotic damage, autophagy inhibition, and deteriorated lung histology. Saro and BrMSCs repaired the lung structure worsened by BLM. Treatments greatly declined the oxidative\/inflammatory markers. The pro-fibrotic TGF-\u00df, \u03b1SMA, and SMAD-3 were decreased. Contrarily, autophagy markers were increased. SMAD-7 and PPAR \u03b1\/\u03b3 were activated denoting their pivotal antifibrotic roles. Co-administration of Saro and BrMSCs revealed the top results. Our findings support the study hypothesis that Saro and BrMSCs can be proposed as potential treatments for IPF.<\/jats:p>","DOI":"10.1007\/s00210-024-03004-y","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T10:02:38Z","timestamp":1708423358000},"page":"5953-5974","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Alleviation of pulmonary fibrosis by the dual PPAR agonist saroglitazar and breast milk mesenchymal stem cells via modulating TGF\u00df\/SMAD pathway"],"prefix":"10.1007","volume":"397","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7105-168X","authenticated-orcid":false,"given":"Seba Hassan","family":"Attia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara F.","family":"Saadawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samaa M.","family":"El-Mahroky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahitab M.","family":"Nageeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,20]]},"reference":[{"issue":"1","key":"3004_CR1","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s40360-021-00524-8","volume":"1; 22","author":"R Akbari","year":"2021","unstructured":"Akbari R, Behdarvand T, Afarin R, Yaghooti H, Jalali MT, Mohammadtaghvaei N (2021) Saroglitazar improved hepatic steatosis and fibrosis by modulating inflammatory cytokines and adiponectin in an animal model of non-alcoholic steatohepatitis. 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Meantime, the study has followed the guidelines of the National Institutes of Health Guide for the care and use of laboratory animals (NIH Publications \u201cNo.8023, revised 1996\u201d). All study procedures complied with the ARRIVE guidelines recommendations. All procedures related to milk sample collection were approved by the institutional review board, Zagazig Faculty of Medicine, Egypt (IRB#: 10119\/20\u201311-2022) and formed following their guidelines. An informed written consent from nursing mothers at the breastfeeding unit in the Pediatrics department, at Zagazig University Hospitals, was taken in the early postpartum period according to the method of Patki et al., <b>[35].<\/b>","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}