<p>Histone deacetylase 3 (HDAC3) is increasingly implicated in Alzheimer’s disease (AD), yet its precise pathogenic role and therapeutic value remain unresolved. This mini-review critically examines the current evidence for HDAC3 in AD, with a focus on what is established, what remains uncertain, and what is needed for translation. We review the data linking HDAC3 to amyloid-β (Aβ) accumulation, Tau pathology, neuroinflammation, and synaptic dysfunction, while highlighting key limitations in the field, including weak causal evidence, inconsistent cell type-specific findings, insufficient human brain validation, and the lack of proof that HDAC3 serves as a central mechanistic node across AD-related pathways. We also discuss major translational challenges, including poor inhibitor selectivity, uncertain brain penetrance, potential safety concerns, and the absence of standardized preclinical benchmarks. We propose that future progress will require human evidence, cell type-specific causal studies, integrated mechanistic models, and more rigorous pharmacological validation. Together, these considerations define a clearer roadmap for evaluating HDAC3 as a biologically credible and clinically actionable target in AD.</p> Graphical abstract <p>HDAC3 upregulation is associated with multiple AD-related pathological processes, including Tau phosphorylation, Aβ accumulation, neuroinflammation, synaptic dysfunction, and cognitive impairment. However, its causal role, cell-type-specific functions, cross-pathway mechanisms, and relevance in human brain tissues remain to be further clarified. This figure was created using BioGDP elements under an academic license.</p>