ScholarWorks@성균관대학교

초록

Signal transducer and activator of transcription 3 (STAT3) is activated by various cytokines including interleukin (IL)-6, IL-17, and IL-23, which have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). STAT3 activation plays a key role in the underlying immunological dysregulation. The efficacy of inhibiting the Janus-activated kinase (JAK)/STAT3 pathway in animal models and patients with lupus is known. However, many existing STAT3 inhibitors lack specificity. Here, we aimed to examine the efficacy of two novel small molecules, Huchembio (HCB)-5009 and HCB-5018, which selectively inhibit STAT3 transcriptional activity, in alleviating disease severity. The potential action mechanism of HCB-5009 and HCB-5018, associated with modulation of STAT3-related signaling and inflammatory cytokines, was investigated in MRL/lpr lupus-prone mice. Twenty-one female MRL/lpr mice were administered treatments over 4 weeks, and the expression of key markers of SLE and proteins were evaluated. Luciferase reporter gene assay was used to assess the effects of the test compounds on STAT signaling pathways in various stable cell lines. Mice treated with the HCB molecules exhibited improvements in lupus symptoms, with decreased levels of anti-dsDNA antibodies and inflammatory cytokines and increased levels of C3 complement. Histopathological analysis of the kidney tissue confirmed that the HCB molecules attenuated inflammation in MRL/lpr mice, suggesting that the STAT3 pathway is involved in lupus progression in mice, and that the observed effects are consistent with modulation of STAT3-related pathways. Collectively, these results suggest that HCB molecules exert therapeutic effects in a lupus mouse model, with effects associated with STAT3 pathway modulation, particularly supported by mechanistic observations for HCB-5018. Further studies, including detailed pharmacokinetic and mechanistic analyses, will be required to fully elucidate their mode of action.

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