Epilepsy is a common chronic neurological disorders with various etiologies and is characterized by abnormal firing of hyperexcitable neurons, leading to dysfunction in the central nervous system (Sun et al., 2023a). Epilepsy can occur at any age, and >68 million people suffer from this condition worldwide (Sandouka and Shekh-Ahmad, 2021; Liang et al., 2023; Chen et al., 2018). Patients with epilepsy often face the threat of somatic and psychiatric disorders, including anxiety, headache, depression, cognitive impairment and behavior disorders (Yu et al., 2023). Unfortunately, there is currently no therapeutic strategy to alter epileptic seizures or prevent, cease, or cure epilepsy (Sultana et al., 2021). Thus, a precise understanding of the potential molecular mechanism of epilepsy is urgently needed, and novel preventive and therapeutic treatments for epilepsy are urgently needed.

Mounting evidence has demonstrated that neuroinflammation is one of the crucial pathophysiological distinguishing features of epilepsy (Yang et al., 2020; Li et al., 2019). As primary immune cells in hippocampal tissue, microglia are the predominant participants in neuroinflammatory processes (Gibbs-Shelton et al., 2023). Abnormally activated microglia is closely related to a variety of nervous system diseases, including epilepsy, through the participation of various key central nervous system functions ranging from vasculogenesis and neurogenesis to synaptic pruning and myelination (Zhuo et al., 2023; Choi et al., 2023; Lu et al., 2023). In particular, hyperactivation of microglia aggravates hippocampal neuronal injury, leading to epileptogenesis through the secretion of proinflammatory mediators, such as tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), as well as the proinflammatory enzyme inducible nitric oxide synthase (iNOS) (Rana and Musto, 2018; Fleisher-Berkovich et al., 2023). Furthermore, hyperactivation of microglia creates a neurotoxic, inflammatory microenvironment in the central nervous system, triggering the pathological process of neurological diseases, such as chronic migraine (Jing et al., 2019), amyotrophic lateral sclerosis (Tsuruta et al., 2023; Peng et al., 2023), and Parkinson's disease (Meng et al., 2024; Wang et al., 2024), especially epilepsy seizure (Xiaoying et al., 2020). Therefore, confirming the molecular mechanisms by which microglial activation influences epileptic seizures has become an important and significant research focus.

Ubiquitin-conjugating enzyme 2C (UBE2C), which is encoded by a gene on chromosome 20q13.12, belongs to the E2 ubiquitin-conjugating enzyme family, also known as ubiquitin-conjugating enzyme 10 (UBCH10) (Presta et al., 2020; Luo et al., 2023). UBE2C not only plays a critical role in the ubiquitination and degradation of intracellular proteins but also participates in the regulation of mitosis and the cell cycle (Zhao et al., 2023; Lei et al., 2020; Jiang et al., 2023). A series of recent studies revealed that UBE2C is a proto-oncogene abnormally upregulated in a variety of human tumor tissues and plays a considerable role in promoting tumorigenesis, dissemination and radiotherapy resistance in a variety of cancer types, such as in brain cancer (Domentean et al., 2023), endometrial cancer (Zhao et al., 2023; Liu et al., 2020), and head and neck squamous cell carcinoma (Zhou et al., 2022; Jin et al., 2020). More importantly, it has been reported that UBE2C expression is dramatically increased in hippocampal tissue and from patients with Alzheimer's disease (Blalock et al., 2011; Li et al., 2022). Functionally, the inhibition of UBE2C was found to mitigate amyloid β pathology and memory deficits in APP/PS1 mice by enhancing microglial autophagy (Li et al., 2022). In addition, Wang et al. reported a significant increase in UBE2C expression in CD45+ microglia extracted from 5 × FAD mice (Wang et al., 2020a). Thus, these studies provide novel insights into the role of UBE2C in neurological disorders. However, the expression and function of UBE2C in epilepsy remain poorly understood.

As the most common type of chemical epigenetic modification, N6-methyladenosine (m6A) modification is a dynamic and reversible posttranscriptional modification that occurs extensively in eukaryotes (Deng et al., 2023; Sun et al., 2023b). Dysregulation of m6A-related protein expression has been observed in the nervous system and is closely associated with the development of epilepsy, Alzheimer's disease, and other neurological disorders (Lv et al., 2023; Zhang et al., 2022). Thus, we investigated whether m6A modification was involved in the regulation of UBE2C expression and thereby mediated epilepsy through microglial activation.

The current research aims to investigate the impact of UBE2C on microglial activation and neuroinflammation in epilepsy and to explore the potential involvement of m6A modification of UBE2C.