Lupus nephritis (LN) is a severe form of systemic lupus erythematosus (SLE), characterized by inflammation in the renal glomeruli and tubules. Previous research has demonstrated that dihydroartemisinin (DHA) can reduce inflammatory damage in LN mouse models. Oxymatrine, which has similar biological properties to DHA, may also provide therapeutic benefits. This study aims to investigate the effects of oxymatrine on LN using a murine model and examines its molecular mechanisms through an analysis of microarray datasets from LN patients. The analysis identified differentially expressed genes (DEGs) in renal tissues, regulated by the transcription factor Yin Yang 1 (YY1), which was found to be significantly upregulated in LN patient kidneys. The results indicate that oxymatrine targets the YY1/IL-6/STAT3 signaling pathway. In cell models simulating renal inflammation, oxymatrine reduced YY1 expression and inhibited the secretion of inflammatory factors (IFs), thereby diminishing inflammation. YY1 is crucial in modulating IFs’ secretion and contributing to LN pathogenesis. Additionally, oxymatrine’s interaction with YY1, leading to its downregulation, appears to be a key mechanism in alleviating LN symptoms. These findings support oxymatrine as a promising therapeutic agent for LN, offering new avenues for treating this autoimmune kidney disorder.

Influenza virus infection remains a major global health burden, with severe disease outcomes driven not only by viral replication but also by excessive host inflammatory responses. Current antiviral therapies predominantly target viral components and fail to adequately control virus-induced hyperinflammation. In this study, we report a dual-target therapeutic strategy integrating direct antiviral activity with host-directed immunomodulation. Using a molecular hybridization approach, we designed and synthesized several dual-target inhibitors simultaneously targeting the influenza virus PB2 cap-binding subunit and host JAK2 kinase. Among them, PB05 emerged as the most promising candidate and was systematically evaluated in vitro and in vivo. PB05 exhibited potent broad-spectrum antiviral activity against influenza A viruses, with nanomolar EC₅₀ values. Mechanistic studies demonstrated that PB05 directly binds to the PB2 cap-binding domain, thereby disrupting viral cap-snatching and RNA synthesis. In parallel, PB05 inhibited JAK–STAT signaling by suppressing STAT2 phosphorylation and downstream ISRE-mediated transcription, leading to a marked reduction in pro-inflammatory cytokine production, including IL-6, IL-1β, and IFN-β, in infected or stimulated immune cells. In a lethal influenza A/PR/8/34 (H1N1) mouse model, oral administration of PB05 at 100 mg/kg (twice daily) markedly decreased lung viral titers, attenuated pulmonary tissue damage and edema, and moderated excessive inflammatory responses. Collectively, these findings identify PB05 as a dual PB2/JAK2 inhibitor that effectively couples antiviral efficacy with immunomodulatory activity, promoting a therapeutic strategy for the treatment of severe influenza and other viral diseases associated with excessive inflammation.