Mollugin inhibits IL-1β production by reducing zinc finger protein 91-regulated Pro-IL-1β ubiquitination and inflammasome activity.

Background: Rubia cordifolia L. has been formally included in the Chinese Pharmacopoeia and utilized for centuries as a traditional Chinese medicine. Mollugin, a quinone compound, is a major active compound extracted from Rubia cordifolia L. Mollugin was reported has multiple pharmacological activity, including anti-inflammatory, anti-tumor effects. However, the anti-inflammatory mechanism is not yet clear. In this study, we explored the anti-inflammatory activity and potential mechanism of mollugin in vitro and in vivo.
Materials and Methods: We explored the mechanisms that mollugin suppressed IL-1β expression through ZFP91 using various assays, including western blot, immunofluorescence, immunoprecipitation, MTT, RT-PCR, and ELISA assays in vitro. In vivo, oral administration of DSS induced colitis in mice and intraperitoneal injection of alum induced peritonitis in mice.
Results: First, the results demonstrated that mollugin dramatically suppressed IL-1β secretion through reducing ZFP91 in macrophages. Crucially, we proved that mollugin inhibited K63-linked Pro-IL-1β ubiquitination through ZFP91 and limitated Pro-IL-1β cleavage efficacy. In addition, ZFP91-mediated Caspase-8 inflammasome component expression was inhibited by mollugin. Furthermore, mollugin inhibited the assembly of the Caspase-8 inflammasome complex by downregulating ZFP91. In vivo studies further revealed that mollugin improved DSS-induced colitis and alum-induced peritonitis in mice by reducing ZFP91. Notely, mollugin significantly altered the abundance of gut flora in DSS-induced colitis mice, which in turn ameliorated the colitis.
Conclusion: We present a novel finding that mollugin inhibition of ZFP91 is a crucial regulatory step, preventing undue inflammatory responses and thereby maintaining immune homeostasis. The current study offers new insight into the development of anti-inflammatory therapeutics targeting ZFP91.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)