Umbilical Moxibustion Enhances Pirfenidone-Mediated Attenuation of Idiopathic Pulmonary Fibrosis by Inhibiting the ZBP1-PANoptosis Pathway

Background This study aims to investigate the ability of umbilical moxibustion (UM) to enhance the pirfenidone (PFD)-mediated attenuation of idiopathic pulmonary fibrosis (IPF) and to explore whether this effect is exerted by inhibition of the ZBP1-PANoptosis pathway. Methods Fifty rats were randomly assigned to five groups ( n = 10/group): Sham, IPF, PFD, UM, and UM + PFD. After a 21-day intervention, pulmonary function was evaluated. Hematoxylin–eosin/Sirius Red staining assessed lung pathology; ELISA measured serum/lung interleukin (IL)-1β, IL-6, IL-18, and IFN-γ; Western blotting detected lung ZBP1, caspase-3, GSDMD-N, and p-MLKL; immunofluorescence observed ZBP1-NLRP3 colocalization. In vitro, cells were divided into N, IPF (100-μM bleomycin), 10% S, 15% S, and 5Z-7 groups. CCK-8 detected cell viability; immunofluorescence observed vimentin/α-SMA intensity; Western blotting detected the same proteins. Results Bleomycin induced increased Rrs, Ers, Rn, and H and decreased Crs and G in rat pulmonary function, along with lung tissue destruction, inflammatory infiltration, collagen deposition, an elevated type I/III collagen ratio, increased levels of inflammatory factors and PANoptosis target proteins, and strong ZBP1-NALP3 colocalization. PFD, UM, and UM + PFD all delayed pulmonary fibrosis progression, improved pulmonary function, and reduced levels of inflammatory factors and PANoptosis target proteins, with UM + PFD showing the optimal effect. In vitro, the UM + PFD group exhibited a ZBP1 inhibitor-like effect, inhibiting PANoptosis and delaying fibrin formation, and its therapeutic effect was positively correlated with serum concentration. Conclusion UM can enhance the ability of PFD to delay IPF. It can alleviate bleomycin-induced pulmonary inflammatory injury and improve pulmonary function of IPF by inhibiting the ZBP1-PANoptosis pathway.