Work

The SIK1-NR4A2 axis: a core driver of epilepsy identified by integrated machine learning and experimental validation

Year: 2026

Type: article

Abstract: Background: Epilepsy remains a major clinical challenge, suggesting that mechanisms beyond the classical excitation-inhibition imbalance contribute to epilepsy. The Liver kinase B1 (LKB1) signaling pathway coordinates energy homeostasis and cell survival, but its key downstream effectors in epilepsy remain largely unknown. Methods: experimental validation. A PTZ-induced status epilepticus rat model, AAV-mediated gene knockdown/overexpression, lentiviral transfection of primary hippocampal neurons, Electroencephalography recording, whole-cell patch-clamp recording, and Western blot analysis were employed to investigate the functional role and molecular mechanisms of candidate genes. Results: Machine learning identified SIK1 (salt-inducible kinase 1) as the top-ranked epilepsy risk gene within the LKB1 pathway. SIK1 expression was significantly upregulated in the hippocampus of SE rats. AAV-mediated SIK1 knockdown prolonged seizure latency and reduced seizure duration, while SIK1 overexpression exacerbated seizure severity. Mechanistically, through PPI network analysis and mediation analysis, we identified NR4A2 as a downstream effector of SIK1. SIK1 negatively regulated NR4A2 expression: SIK1 knockdown increased NR4A2, whereas SIK1 overexpression decreased NR4A2. Rescue experiments showed that co-overexpression of SIK1 and NR4A2 reversed the pro-epileptic effect of SIK1 alone. Whole-cell patch-clamp recordings demonstrated that SIK1 knockdown or NR4A2 overexpression restored action potential amplitude to near-normal levels in magnesium-free-treated neurons. Conclusion: SIK1 negatively regulates NR4A2, and restoring NR4A2 expression counteracts SIK1-induced neuronal hyperexcitability. These findings suggest that targeting the SIK1-NR4A2 axis may represent a potential therapeutic strategy for epilepsy.

Source: Frontiers in Cell and Developmental Biology

DOI: 10.3389/fcell.2026.1887268