2. Academic Validation
  3. Platycodin D alleviates idiopathic pulmonary fibrosis by targeting PPP2R1A and regulating the PP2A-mediated PI3K/Akt pathway to inhibit fibroblast transdifferentiation

Platycodin D alleviates idiopathic pulmonary fibrosis by targeting PPP2R1A and regulating the PP2A-mediated PI3K/Akt pathway to inhibit fibroblast transdifferentiation

  • Phytomedicine. 2026 Apr:153:158000. doi: 10.1016/j.phymed.2026.158000.
Jia-Ning Gong 1,  Zan Cui 2,  Yuan-Yuan Liu 3,  Ling-Qi Meng 4,  Yi Wang 5,  Jia Shi 2,  Zhi-Yong Qin 3,  Guang Chen 3,  An Chang 6
Affiliations

Affiliations

  • 1 Intensive Care Unit, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China.
  • 2 Department of Drug Administration, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China.
  • 3 School of Pharmacy, Jinzhou Medical University, Jinzhou, 121000, China.
  • 4 Pain Management Department, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China.
  • 5 Key Surgical Laboratory of Educational Administration of Liaoning Province, Jinzhou Medical University, Jinzhou, 121000, China.
  • 6 Department of Drug Administration, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China; Key Surgical Laboratory of Educational Administration of Liaoning Province, Jinzhou Medical University, Jinzhou, 121000, China. Electronic address: [email protected].
PMID: 41759424 DOI: 10.1016/j.phymed.2026.158000
Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is driven by the transdifferentiation of pulmonary fibroblasts into myofibroblasts, a pivotal step in disease progression. This study aimed to determine whether platycodin D (PD), a natural compound used in traditional Chinese medicine, can inhibit this process. The findings revealed that PD alleviates lung injury, reduces inflammation and oxidative stress, and markedly suppresses myofibroblast generation in both in vivo and in vitro models.

Objective: To clarify the potential of PD to inhibit myofibroblast generation and activation, which are pertinent for alleviating IPF, and to explore the associated targets and molecular mechanisms.

Methods: IPF models were used to assess the effects of PD on inflammation, oxidative stress, and fibroblast‑to‑myofibroblast transdifferentiation. Core targets and mechanisms were identified using a comprehensive assay, which comprised transcriptome analysis and the Lip‑SMap technology. Molecular docking, molecular dynamics simulations, cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), and functional recovery experiments were performed to validate the direct targets of PD and elucidate its anti‑IPF molecular actions.

Results: The findings revealed that PD mitigates murine lung injury, inhibits systemic and pulmonary inflammation, reduces oxidative stress, and significantly suppresses fibroblast transdifferentiation. Integrated transcriptomics and Lip‑SMap identified that PPP2R1A is a critical target regulating the PI3K/Akt pathway, suggesting a mechanistic basis for the anti‑IPF effects of PD. Subsequent molecular docking, molecular dynamics simulations, CETSA, and SPR confirmed that PPP2R1A is a direct target of PD. Small interfering RNA knockdown and functional recovery assays demonstrated that PD binds PPP2R1A, stabilizes and activates protein Phosphatase 2A (PP2A), and thereby inhibits PI3K/Akt signaling. This inhibition is likely the mechanism by which PD blocks myofibroblast transdifferentiation.

Conclusion: PD may at least partially inhibit the PI3K/Akt signaling pathway by directly targeting PPP2R1A to stabilize and activate PP2A, thereby suppressing myofibroblast transdifferentiation and alleviating IPF.

Keywords

Fibroblasts; Idiopathic pulmonary fibrosis; Myofibroblasts; PI3K/Akt signaling pathway; PPP2R1A; Platycodin D; Transdifferentiation.

Figures
Products