Oridonin alleviates SiNPs-induced pulmonary fibrosis by inhibiting pyroptosis via IRE1α-XBP1s-NLRP3 pathway

Objective: Oridonin, a tetracyclic diterpenoid derived from Rabdosia rubescens (Donglingcao), exhibits beneficial effects such as lowering blood pressure, antioxidant activity, and immune enhancement. Long-term exposure to silica nanoparticles (SiNPs) is known to induce pulmonary fibrosis, associated with endoplasmic reticulum stress and pyroptosis; however, the interaction between SiNPs and Pyroptosis remains unreported. The mechanisms underlying the antifibrotic effects of oridonin require further investigation.

Methods: In vivo, the antifibrotic and anti-pyroptosis effects of oridonin were evaluated in a SiNPs-induced pulmonary fibrosis murine model. To further elucidate the mechanisms through which oridonin attenuates SiNPs-induced Pyroptosis, in vitro studies were conducted using the immortalized mouse alveolar macrophage cell line MH-S.

Results: Endoplasmic reticulum stress and Pyroptosis were observed in both in vivo (SiNPs-induced pulmonary fibrosis murine model) and in vitro (MH-S cell line) systems. Network pharmacology analysis identified IRE1α and NLRP3 as potential targets of oridonin. Consistent with these findings, oridonin significantly attenuated silica nanoparticle (SiNPs)-induced endoplasmic reticulum stress, Pyroptosis, and pulmonary fibrosis in both experimental models. Pharmacological inhibition of IRE1α with 4μ8c and NLRP3 with MCC950 demonstrated that IRE1α-mediated endoplasmic reticulum stress directly activates NLRP3-dependent Pyroptosis.

Conclusions: Collectively, our findings demonstrate that endoplasmic reticulum stress activates Pyroptosis via the IRE1α-XBP1s-NLRP3 axis, while oridonin attenuates both processes through dual targeting of IRE1α and NLRP3, respectively.

Alveolar macrophages; Endoplasmic reticulum stress; IRE1α-XBP1s-NLRP3; Oridonin; Pyroptosis.