xiaowei liang lab data
Description
Lignans are a class of natural estrogens with unique structures and diverse biological activities. However, limitations in their synthetic methods and the unknown nature of their molecular targets have hindered their drug development. Our study establishes a highly efficient biomimetic catalytic system based on blue-copper laccases, enabling the large-scale synthesis of the lignan derivative XYD622 (8). At the cellular level, XYD622 significantly induced apoptosis in keratinocytes and inhibited the expression of psoriasis-related inflammatory factors. In an imiquimod (IMQ)-induced psoriatic mouse model, topical administration of XYD622 effectively reduced skin inflammation, epidermal thickening, and immune cell infiltration. Using LiP-MS and BLI, we identified pyruvate kinase M2 (PKM2) as the direct target of XYD622. Mechanistic studies revealed that XYD622 directly binds to PKM2 and inhibits its activity, thereby downregulating overactive glycolysis in keratinocytes and blocking the nuclear translocation of PKM2. Finally, we found that PKM2 was highly expressed in psoriatic keratinocytes alongside an excessive glycolysis level, suggesting the potential of XYD622 as a therapeutic agent for human psoriasis. Our study developed a biomimetic catalytic synthesis method for lignans and revealed a new mechanism by which lignans regulate the immune-metabolic pathway by targeting PKM2, providing new candidate drugs and a theoretical basis for the treatment of psoriasis.
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Institutions
- Xiangya Hospital Central South UniversityHunan, Changsha