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

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.