Nanoliposomal Eucommia ulmoides extract limits PANoptosis in sepsis-induced acute lung injury through a TGF-β1-JNK pathway.

BACKGROUND AND PURPOSE: Sepsis-induced acute lung injury (ALI) is driven by macrophage-mediated inflammation and PANoptosis. Eucommia ulmoides Oliv. (Du Zhong, DZ) contains anti-inflammatory phytochemicals, but crude extracts show poor solubility, rapid clearance and a narrow therapeutic window. We therefore tested whether a nanoliposomal DZ formulation (Nano-LP-DZ) could improve efficacy in experimental sepsis-induced ALI. EXPERIMENTAL APPROACH: Nano-LP-DZ was prepared by double-emulsion ultrasonication and characterised physicochemically. Its effects were evaluated in lipopolysaccharide-stimulated macrophages, macrophages stimulated with Oxo plus lipopolysaccharide, and in mice subjected to caecal ligation and puncture (CLP). Cytokine release, lung injury and macrophage survival were assessed together with markers of pyroptosis, apoptosis and necroptosis. Upstream regulation was examined using TGF-β1 knockdown, TGF-β receptor blockade, JNK inhibition, and transcriptomic analyses. KEY RESULTS: Compared with the unformulated extract, Nano-LP-DZ preserved macrophage viability at pharmacologically active concentrations, more effectively reduced interleukin-1β, interleukin-6 and tumour necrosis factor-α release, and alleviated CLP-induced lung oedema, neutrophil infiltration and histopathological damage. Nano-LP-DZ restored TGF-β1 expression in macrophages under septic stress and induced phosphorylation of JNK and its substrate Bim. These changes were accompanied by suppression of PANoptosis, with reduced caspase-1, gasdermin D and E, caspase-8, caspase-3, caspase-7 and phospho-MLKL signalling. Silencing TGF-β1, blocking its receptor or inhibiting JNK markedly inhibited these protective effects. CONCLUSIONS AND IMPLICATIONS: Nano-LP-DZ broadens the therapeutic window and enhances the anti-inflammatory efficacy of DZ in sepsis-induced ALI by engaging a macrophage TGF-β1-JNK pathway that restrains PANoptosis. These findings identify TGF-β1-JNK as a druggable upstream checkpoint in sepsis-associated lung injury.