Human Brain Organoids for Studying General Anesthetic Mechanisms: Developmental Vulnerability, Cellular Stress, and...

General anesthetics are indispensable for surgical procedures, procedural sedation, and intensive care, but their mechanisms of action in the human brain are not fully understood. Classical biochemical approaches have delineated key targets of general anesthetics, such as GABAA and NMDA receptors, ion channels, mitochondria, neurotransmission, and inflammatory pathways. However, animal models and two-dimensional cultures do not represent human-specific neurodevelopment, regional cellular diversity, or three-dimensional brain architecture. Human brain organoids offer a complementary system to investigate anesthetic effects during human development. Recent reports on cerebral, forebrain, and midbrain organoids indicate that propofol and sevoflurane may affect neural progenitor cell proliferation, neuronal differentiation, apoptosis, autophagy, mitochondrial metabolism, long non-coding RNA networks, synaptic gene programs, and regionspecific maturation. These results do not preclude clinically required anesthesia, particularly as large-scale human studies have failed to demonstrate deficits in general intelligence following single short-term exposures. Rather, organoid models help establish which types of neural cells, developmental stages, and molecular mechanisms might be vulnerable to anesthesia. This review highlights recent advances in organoid-based research on the mechanisms of general anesthesia, particularly for propofol and volatile anesthetics. It also explores how region-specific organoids, assembloids, vascularized systems, microglia-enriched models, and multi-omics techniques may help resolve developmental vulnerability and aid more targeted translational studies of anesthesia.