The Fungal‐Derived Natural Compound Chaetosemin J Exerts Antiepileptic Effects by Inhibiting Neuronal Apoptosis via the Extracellular Matrix/Focal Adhesion Signaling Pathway

Fungal-derived natural compounds serve as a crucial resource for new drug development and have witnessed significant progress in recent years. Researchers have screened multiple bioactive compounds from fungal extracts. Epilepsy, a neurological disorder affecting tens of millions of people worldwide, presents substantial therapeutic challenges due to its complex pathogenesis. Neuronal apoptosis plays a critical role in epileptogenesis and seizure generation. In this study, we screened a fungal-derived natural compound, chaetosemin J, with antiepileptic activity using zebrafish and cell models. Screening assays using the zebrafish model demonstrated that chaetosemin J alleviated epileptiform behavior and downregulated seizure-induced epilepsy marker genes. In parallel, cell-based assays showed that chaetosemin J enhanced cell viability. The anti-epileptic pathways and associated targets of chaetosemin J were predicted using transcriptomics and molecular docking techniques. Furthermore, its anti-epileptic mechanism was validated through real-time quantitative polymerase chain reaction experiments and calcium ion reflow assays. Collectively, our findings suggested that chaetosemin J may alleviate epileptic seizures by downregulating the expression of integrin-related genes in the extracellular matrix/focal adhesion signaling pathway, reversing the abnormal elevation of intracellular calcium ion concentration during epileptic seizures, and thereby reducing the activation of the apoptosis-related factor Calpain-2. This study provides a new candidate molecule for the development of antiepileptic drugs.