# Phillyrin alleviates Kawasaki disease-induced lung inflammation by inhibiting platelet production through the NLRP3/IL-1β/NF-E2 signaling pathway

## TL;DR

Phillyrin reduces lung inflammation in Kawasaki disease by blocking platelet production through the NLRP3/IL-1β/NF-E2 pathway.

## Contribution

This study is the first to explore phillyrin's therapeutic potential in Kawasaki disease-induced lung inflammation and its mechanism of action.

## Key findings

- Phillyrin dose-dependently reduced platelet counts and lung inflammation in a mouse model of Kawasaki disease.
- Phillyrin inhibited the NLRP3/IL-1β axis, leading to decreased NF-E2 expression and suppressed platelet production.
- Phillyrin's effects were enhanced in NLRP3-knockout mice and MEG-01 cells with NLRP3 inactivation.

## Abstract

The management of Kawasaki disease (KD)-associated complications, including thrombocytosis-driven lung inflammation, remains a clinical challenge, necessitating novel therapeutic exploration. Phillyrin, a principal bioactive compound from Forsythia suspensa (Thunb.) Vahl, has shown therapeutic promise in viral lung inflammation. However, its potential therapeutic effect and mechanism of action in KD-induced lung injury are entirely unexplored.

This study was designed to explore the therapeutic potential of phillyrin against KD-induced thrombocytosis and lung inflammation and its mechanism of action.

C57BL/6 mice and NLRP3 knockout mice were intraperitoneal injected with Lactobacillus casei cell wall extract (LCWE) to establish models of KD-induced lung inflammation. MEG-01 cells were also stimulated with LCWE, and subsequently intervened with phillyrin and NLRP3 inhibitor MCC950. The therapeutic effects and mechanisms of phillyrin werestudied both in vivo and in vitro.

In the LCWE-induced mice lung inflammation model, phillyrin dose-dependently decreased circulating platelet counts and reduced CD61⁺ platelets in lung tissue. Hematological analysis demonstrated that phillyrin administration led to a significant reduction in white blood cell count. Furthermore, histopathological examination revealed attenuated inflammatory infiltration and fewer F4/80⁺ macrophages in lung sections. Bioinformatic and molecular docking analyses indicated a strong association between phillyrin's effects and the NLRP3/IL-1β axis. Mechanistic studies demonstrated that phillyrin suppressed megakaryocyte-derived platelet production by inhibiting NLRP3 inflammasome-mediated IL-1β secretion, which consequently disrupts IL-1β-driven NF-E2 expression and leads to substantial downregulation of NF-E2. Furthermore, the suppressive effects of phillyrin on megakaryocytic platelet generation and pulmonary inflammation were consistently enhanced in NLRP3-knockout mice, as well as in MEG-01 cells following either NLRP3 inactivation or IL-1 receptor antagonist treatment.

Phillyrin significantly attenuated LCWE-induced lung inflammation and suppressed megakaryocyte-derived platelet production by inhibiting the NLRP3/IL-1β axis, thereby impeding IL-1β-mediated NF-E2 expression and subsequent thrombopoiesis. These findings identify Phillyrin as a promising therapeutic candidate for Kawasaki disease by targeting the NLRP3/IL-1β/NF-E2 pathway to ameliorate pathological platelet overproduction and pulmonary complications.

Phillyrin significantly alleviated LCWE-induced pulmonary inflammation by suppressing megakaryocyte-derived platelet production. Mechanistically, phillyrin inhibited the activation of the NLRP3 inflammasome, thereby impeding caspase-1 maturation and IL-1β secretion. The blockade of IL-1β binding to its receptor consequently downregulated the expression of NF-E2, a pivotal transcription factor regulating platelet production.

The online version contains supplementary material available at 10.1186/s13020-026-01348-6.