Temporal lobe epilepsy (TLE), the most common form of epilepsy, is primarily characterized by hippocampal sclerosis (HS). Microglia reactivity is a critical component of TLE pathogenesis, and apolipoprotein E (APOE) may be a potential mediator of these processes. However, its role in TLE progression remains unclear. Bioinformatics approaches with biomarker validation are integrated to elucidate APOE's role and hippocampal microglia in the mechanisms underlying TLE. APOE expression is significantly elevated in the hippocampal tissues of patients with TLE‐HS and in TLE mouse models. Single‐cell RNA sequencing reveals a subset of microglia with high APOE gene expression, which serves as the principal carrier of increased APOE during disease progression. Bioinformatic analyses, in vitro studies, and in vivo functional experiments utilizing TLE mouse models implicate these APOE ‐expressing microglia in regulating microglial differentiation, promoting neuroinflammation, neuronal apoptosis, and enhancing neuronal excitability. Genetic knockout of APOE mitigates gliosis, neuronal cell death, and seizure frequency in the hippocampus of epileptic mice. Additionally, APOE expression primarily induces significant alterations in glycerophospholipid metabolism and its associated metabolic derivatives within the epileptic microenvironment. Overall, APOE ‐expressing microglia are pivotal drivers of HS and TLE progression, positioning APOE and its downstream signaling pathways as promising therapeutic TLE targets.

Rationale: Immune checkpoint inhibitors, particularly programmed cell death protein 1 (PD-1) blockers, have transformed cancer therapy but can induce immune-related endocrine toxicities. Severe involvement of multiple endocrine axes, including dual pituitary dysfunction, is rare and challenging to diagnose due to nonspecific clinical features. Highlighting such cases can improve early recognition and management. Patient concerns: A 56-year-old man with esophageal cancer developed fatigue, polyuria, polydipsia, dizziness, and severe hyponatremia after treatment with tislelizumab, a PD-1 inhibitor. Diagnoses: Laboratory evaluation revealed new-onset autoimmune diabetes, hypothyroidism, and secondary adrenal insufficiency. The constellation of biochemical abnormalities and clinical features, in the absence of alternative etiologies, indicated immune-related hypophysitis and pancreatic islet injury. Two additional cases of severe, recurrent hyponatremia after PD-1 therapy were also reviewed. Interventions: The patient received targeted hormone replacement therapy, including glucocorticoids and levothyroxine, along with insulin for glycemic control. Outcomes: Symptoms improved significantly, and biochemical parameters normalized following treatment, demonstrating effective management of multi-glandular endocrine failure induced by PD-1 blockade. Lessons: PD-1 inhibitors can cause severe, concurrent dysfunction of multiple endocrine organs. Clinicians should maintain high vigilance, implement proactive screening for pituitary and metabolic abnormalities during and after immune checkpoint inhibitor therapy, and adopt a multidisciplinary approach to ensure timely diagnosis and treatment.