Lathyrol Exerts Anti-Pulmonary Fibrosis Effects by Activating PPARγ to Inhibit the TGF-β/Smad Pathway

Sep 30, 2026

Uploaded by Jacob

Idiopathic pulmonary fibrosis is a chronic, progressive interstitial lung disease lacking specific and effective drug therapies. Lathyrol, a diterpene from the traditional Chinese medicine Leptochloa chinensis, was evaluated for anti-pulmonary fibrosis activity and mechanism. In vivo, bleomycin-induced mouse pulmonary fibrosis received intraperitoneal lathyrol, and in vitro fibroblast lines were challenged with TGF-β1 before treatment. Lathyrol activated PPARγ, promoted ubiquitination of phosphorylated Smad3, enhanced Nedd4–PPARγ–Smad3 interaction, suppressed TGF-β/Smad signaling, reduced myofibroblast transformation, and its benefits were blocked by PPARγ inhibition or gene silencing.

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Abstract

Introduction

Article Lathyrol Exerts Anti-Pulmonary Fibrosis Effects by Activating PPARγ to Inhibit the TGF-β/Smad Pathway Qian Zeng 1,†, Min-Lin Liao 1,†, Yu-Yang Luo 1, Shuang Li 1, Gao You 1, Chong-Mei Huang 2, Min-Hui Liu 2, Wei Liu 1, * and Si-Yuan Tang 2, * Academic Editor: Bernhard Biersack Received: 4 December 2025 Revised: 20 December 2025 Accepted: 23 December 2025 Published: 30 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Xiangya Nursing School, Central South University, 172 Tongzipo Road, Changsha 410013, China; [zengqian02@csu.edu.cn](zengqian02@csu.edu.cn) (Q.Z.); [liaominlin120@csu.edu.cn](liaominlin120@csu.edu.cn) (M.-L.L.); [227811043@csu.edu.cn](227811043@csu.edu.cn) (Y.-Y.L.); [247811054@csu.edu.cn](247811054@csu.edu.cn) (S.L.); [257811045@csu.edu.cn](257811045@csu.edu.cn) (G.Y.) 2 School of Nursing, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750003, China; [chongmeihuang@nxmu.edu.cn](chongmeihuang@nxmu.edu.cn) (C.-M.H.); [liuminhui@nxmu.edu.cn](liuminhui@nxmu.edu.cn) (M.-H.L.) * Correspondence: [liuw079@csu.edu.cn](liuw079@csu.edu.cn) (W.L.); [sytang263@csu.edu.cn](sytang263@csu.edu.cn) (S.-Y.T.); Tel.: +86-13975187895 (W.L.);+86-15874107355 (S.-Y.T.) † These authors contributed equally to this work. Abstract Idiopathic pulmonary fibrosis is a chronic, progressive, interstitial lung disease for which specific and effective drug therapies are still lacking. Lathyrol is a diterpene compound with broad pharmacological activities that can be extracted from the traditional Chinese medicine Leptochloa chinensis (L.) Nees. To investigate the anti-pulmonary fibrosis effect of lathyrol and its underlying mechanism. In vivo, a mouse model of pulmonary fibrosis was induced by bleomycin, treated with intraperitoneal injections of lathyrol. In vitro, myofibroblast conversion was induced in three fibroblast cell lines by stimulating them with TGF-β1, followed by treatment with lathyrol. Transcriptomic analysis was performed to assess the regulation of signaling pathways and gene expression patterns modulated by lathyrol. The effects of lathyrol on PPARγ activation, as well as on the nuclear translocation and ubiquitination of phosphorylated Smad3, were examined. The interaction among Nedd4, PPARγ, and phosphorylated Smad3 was detected. In vivo, lathyrol ameliorated pathological fibrosis in the lungs of mice with pulmonary fibrosis and this effect was blocked by a PPARγ inhibitor. In vitro, lathyrol inhibited the transdifferentiation of fibroblasts into myofibroblasts, and these effects were suppressed by either inhibiting PPARγ activation or specifically silencing the PPARγ gene. Lathyrol inhibited the nuclear translocation of phosphorylated Smad3 and promoted its ubiquitination, while also enhancing the interaction among Nedd4, PPARγ, and phosphorylated Smad3 . These effects were abolished following the specific silencing of either PPARγ or Nedd4 . In conclusion, Lathyrol inhibits myofibroblast transformation by suppressing TGF-β/Smad pathway activation through PPARγ activation, thereby exerting its anti-pulmonary fibrosis effects. Keywords: pulmonary fibrosis; lathyrol; PPARγ; TGF-β/Smad signaling pathway 1. Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease of unknown etiology [1], characterized by remodeling of the pulmonary interstitium, distal airways, and alveolar spaces [2] . IPF is an age-related disease with sharply increasing incidence with age, reflected by a median survival of only 3–5 years [3] . With the progressive aging of the global population, the clinical and socioeconomic burden of the disease on both patients and healthcare systems is steadily increasing [4] . Currently, the drugs used clinically to treat the disease are pirfenidone and ninteda

FAQs

What is the main therapeutic goal of the study?

To determine whether lathyrol can exert anti-pulmonary fibrosis effects and to clarify its underlying mechanism.

How was pulmonary fibrosis modeled for in vivo testing?

A mouse model of pulmonary fibrosis was induced by bleomycin, followed by intraperitoneal lathyrol treatment.

What pathway does lathyrol target according to the results?

Lathyrol inhibits pulmonary fibrosis by activating PPARγ and thereby suppressing the TGF-β/Smad pathway, including effects on phosphorylated Smad3 nuclear translocation and ubiquitination.

Sep 30, 2026

Uploaded by Jacob