BACKGROUND

Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), lacks effective therapies because of its complex pathogenesis. PANoptosis, an integrated cell death pathway that combines apoptosis, pyroptosis, and necroptosis, has been implicated in inflammatory diseases; however, its role in LN and potential as a therapeutic target remain unexplored. Total glucosides of paeony (TGP), a traditional Chinese medicine derived from Paeonia lactiflora Pall, has shown promise in LN treatment due to its immunomodulatory and anti-inflammatory properties. Nevertheless, the mechanisms underlying its renoprotective effects, particularly its potential regulation of PANoptosis, are poorly understood.

PURPOSE

This study investigated the role of PANoptosis in LN pathogenesis and elucidated the therapeutic mechanisms of TGP, focusing on ZBP1-mediated podocytes PANoptosis.

METHODS

Four mRNA microarray datasets of renal tissues from patients with LN and LN mouse models were obtained from the GEO database, and were performed with gene set enrichment analysis (GSEA) to identify PANoptosis-related pathways. Renal pathology was assessed using HE staining and proteinuria detection. Cell death was evaluated in vivo using TUNEL staining and in vitro through flow cytometry and LDH release assay. The protein levels of ZBP1 and PANoptosis markers were detected by immunoblotting and immunohistochemistry (IHC).

RESULTS

PANoptosis-related pathways were significantly enriched in LN kidneys. TGP treatment suppressed podocytes PANoptosis and alleviated renal injury in MRL/lpr mice. Mechanistically, TGP inhibited PANoptosis by regulating the STAT2-ZBP1 axis, with ZBP1 identified as a pivotal regulator. ZBP1 overexpression attenuated the therapeutic effects of TGP, confirming its central role in LN pathogenesis.

CONCLUSION

This study reveals ZBP1-mediated podocytes PANoptosis as a key mechanism in LN and establishes TGP as a promising therapeutic agent targeting this pathway. These findings provide a novel, clinically translatable strategy for LN treatment.