Advancing the Paradigm of Temporal Lobe Epilepsy as a Network Disease: The Promise of Biomarkers and Targeted Disease Modification.

Temporal lobe epilepsy (TLE) is increasingly conceptualized not as an isolated hippocampal lesion, but as a complex, multiscale limbic network connectomic disorder. Despite advances in pharmacological management, over 30% of patients experience drug-resistant epilepsy, underscoring the urgent need to shift from symptomatic seizure control to mechanism-directed disease modification. This review comprehensively synthesizes the pathophysiological architecture of epileptogenesis in TLE, spanning mitochondrial bioenergetic alterations, chronic neuroinflammation, synaptic reorganization, and ionic plasticity resulting from ion-channel dysregulation. We evaluate diagnostic advancements, highlighting how invasive stereo-EEG disambiguates pathological high-frequency oscillations from physiological ripples, how structural HARNESS-MRI maps anatomical substrates, and how AI-driven algorithms analyze ultra-long-term EEG streams for continuous seizure forecasting. Additionally, peripheral biofluid proteins and microRNAs provide noninvasive windows into active neuroinflammation and network remodeling, serving as valuable tools for longitudinal disease monitoring rather than primary screening. Therapeutically, the field is evolving beyond empirical antiseizure medications toward mechanism-based rational drug design and precision interventions. Dual-mechanism agents enhance seizure freedom, while antisense oligonucleotides, microRNA antagomirs, and cation-chloride cotransporter modulators target underlying genetic and biophysical drivers. Minimally invasive ablation, AI-guided closed-loop neuromodulation, targeted anti-inflammatory biologics, and patient-derived 3D cerebral organoid platforms further expand the translational frontier. Ultimately, bridging these experimental modalities through prospective clinical validation may provide a viable path toward interrupting epileptogenesis and realizing true disease modification in human TLE.