ArticlePloS one2011
PPAR-γ ligands repress TGFβ-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
110 citing papers in PubMed, 1 synthesis or guideline pooled it, 187 citations in OpenAlex.
- A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility.Arthritis research & therapy · 2014Pooled it
- Epidermal PPARγ Signaling as a Suppressor of Toll-like Receptor-Mediated Inflammation and Fibrosis: Relevance to Cutaneous Squamous Cell Carcinoma.International journal of molecular sciences · 2026Article
- Hibernating bear serum triggers an anti-fibrotic signature in human fibroblasts, involving ECM remodeling and MAPK signaling activation.Scientific reports · 2026Article
- TGF-beta inhibitors in cancer therapy: a review of the TGF-beta signal transduction pathway and current developments.EXCLI journal · 2026Review
- Nanocarrier-Enabled siRNA Therapy for Pulmonary Fibrosis: Pharmacological Rationale, Delivery Barriers, and Translational Opportunities.International journal of nanomedicine · 2026Review
- Macrophages and Pulmonary Fibrosis.Current molecular medicine · 2025Review
- Xinfeng Capsule inhibits oxidative stress via regulating the PPARγ/ Hmgcs2 signaling pathway in lung tissue of adjuvant arthritis rats.Frontiers in pharmacology · 2025Article
- Possible Combinatorial Utilization of Phytochemicals and Extracellular Vesicles for Wound Healing and Regeneration.International journal of molecular sciences · 2024Review
- Review
- Piezo1 Activation Drives Enhanced Collagen Synthesis in Aged Animal Skin Induced by Poly L-Lactic Acid Fillers.International journal of molecular sciences · 2024Article
- MicroRNAs regulating signaling pathways in cardiac fibrosis: potential role of the exercise training.American journal of physiology. Heart and circulatory physiology · 2024Review
- Anoctamin-1 is induced by TGF-β and contributes to lung myofibroblast differentiation.American journal of physiology. Lung cellular and molecular physiology · 2024Article
- Anoctamin-1 is induced by TGF-beta and contributes to lung myofibroblast differentiation.bioRxiv : the preprint server for biology · 2023Article
- Asarinin attenuates bleomycin-induced pulmonary fibrosis by activating PPARγ.Scientific reports · 2023Article
- The Role of Autophagy and Apoptosis in Affected Skin and Lungs in Patients with Systemic Sclerosis.International journal of molecular sciences · 2023Review
- Towards a Unified Approach in Autoimmune Fibrotic Signalling Pathways.International journal of molecular sciences · 2023Review
- Inositol possesses antifibrotic activity and mitigates pulmonary fibrosis.Respiratory research · 2023Article
- Article
- Appraisal of the Possible Role of PPARPPAR research · 2023Article
- Immunologic and imaging signatures in post tuberculosis lung disease.Tuberculosis (Edinburgh, Scotland) · 2022Review
50 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Transforming growth factor beta (TGFβ) induced differentiation of human lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary fibrosis. Although the typical TGFβ signaling pathway involves the Smad family of transcription factors, we have previously reported that peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands inhibit TGFβ-mediated differentiation of human lung fibroblasts to myofibroblasts via a Smad-independent pathway. TGFβ also activates the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway leading to phosphorylation of Akt(S473). Here, we report that PPAR-γ ligands, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and 15-deoxy-(12,14)-15d-prostaglandin J(2) (15d-PGJ(2)), inhibit human myofibroblast differentiation of normal and idiopathic pulmonary fibrotic (IPF) fibroblasts, by blocking Akt phosphorylation at Ser473 by a PPAR-γ-independent mechanism. The PI3K inhibitor LY294002 and a dominant-negative inactive kinase-domain mutant of Akt both inhibited TGFβ-stimulated myofibroblast differentiation, as determined by Western blotting for α-smooth muscle actin and calponin. Prostaglandin A(1) (PGA(1)), a structural analogue of 15d-PGJ(2) with an electrophilic center, also reduced TGFβ-driven phosphorylation of Akt, while CAY10410, another analogue that lacks an electrophilic center, did not; implying that the activity of 15d-PGJ(2) and CDDO is dependent on their electrophilic properties. PPAR-γ ligands inhibited TGFβ-induced Akt phosphorylation via both post-translational and post-transcriptional mechanisms. This inhibition is independent of MAPK-p38 and PTEN but is dependent on TGFβ-induced phosphorylation of FAK, a kinase that acts upstream of Akt. Thus, PPAR-γ ligands inhibit TGFβ signaling by affecting two pro-survival pathways that culminate in myofibroblast differentiation. Further studies of PPAR-γ ligands and small electrophilic molecules may lead to a new generation of anti-fibrotic therapeutics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.