Silybin, silychristin and silydianin are potential novel plant-based Pannexin1 channel inhibitors

Pannexin1 (Panx1) channels are crucial for cellular communication, and their abnormal opening is linked to inflammation and cell death. Developing novel inhibitors for these channels represents a promising therapeutic approach. Silymarin, the biologically active mixture derived from Silybum marianum L. Gaertn, and its major bioactive flavonolignans, namely silybin, silychristin, and silydianin, have been identified as potential therapeutics for the treatment of several Panx1 channel-associated diseases. This study investigates the potential inhibitory effects of silymarin and its components on Panx1 channel activity through in vitro and in silico approaches. In vitro testing demonstrated that silybin, silychristin, and silydianin potentially inhibited Panx1 channel-related activity by reducing the extracellular adenosine triphosphate levels without altering the Panx1 protein expression. Additionally, silybin reduced interleukin-1 beta levels and alleviated NLRP3 inflammasomelinked cell death. In silico modelling confirmed the in vitro results by identifying the potential Panx1-binding affinity of these components and their ability to reduce the Panx1 channel pore diameter. Overall, this study provides evidence for the potential Panx1 channel inhibitory properties of silybin, silychristin, and silydianin, and suggests a novel alternative therapeutic mechanism of these compounds based on Panx1 channel inhibition.