HMC3 revealed: how much do these "Microglia" really tell us?

Microglia are a key driver of neurodegenerative disease, orchestrating inflammatory signaling, metabolic stress responses, synaptic remodeling, and neuronal fate within the central nervous system (CNS). Among experimental models, the human microglial cell line, HMC3, is one of the most widely used models for mechanistic investigation and pharmacological screening of microglial dysfunction, particularly in neurodegenerative contexts. Nevertheless, a key question remains: how faithfully does HMC3 reflect human microglial biology? This review integrates current evidence on HMC3 cells, including their molecular and metabolic features, functional plasticity, and disease-oriented applications. HMC3 cells reproduce hallmark neurodegeneration-associated programs, such as stimulus-dependent polarization, oxidative and endoplasmic reticulum stress signaling, inflammasome activation, autophagy dysregulation, lipid remodeling, angiogenic cross-talk, and phagocytic clearance of amyloid and apoptotic debris, modeling processes relevant to Alzheimer's disease, Parkinson's disease, ischemic injury, and metabolic neurodegeneration. Neuron-microglia co-culture systems further demonstrate the direct impacts of HMC3 activation states on neuronal vulnerability and survival. We also summarize the expanding repertoire of pharmacological and genetic interventions applied to HMC3, highlighting their compatibility with high-throughput and multi-omics discovery platforms. Despite inherent limitations of immortalized models, HMC3 represents a powerful front-line tool for dissecting neurodegenerative microglial mechanisms and steering early therapeutic discovery.