HDDC3 (HD domain containing 3) encodes a ppGpp hydrolase enzyme, the metazoan ortholog of bacterial SpoT protein 1. The protein contains an active site for ppGpp hydrolysis and a conserved His-Asp-box motif for Mn2+ binding, efficiently catalyzing guanosine 3',5'-diphosphate (ppGpp) hydrolysis both in vitro and in vivo 1. HDDC3 functions in starvation response pathways; deletion in Drosophila induces retarded body growth and impaired starvation resistance 1. Recent evidence demonstrates that ppGpp accumulates in animal cells and triggers metabolic changes, cell death, and lethality, establishing a ppGpp-dependent stringent response in metazoans 2. Beyond metabolic regulation, HDDC3 demonstrates clinical relevance as a differentially expressed gene associated with ischemic stroke risk, identified as a feature gene in predictive nomograms 3, and serves as a diagnostic biomarker for polycystic ovary syndrome (PCOS) with high discriminatory power (AUC: 0.918) 4. In PCOS, HDDC3 expression positively correlates with immune regulatory cells including T regulatory cells, activated mast cells, and monocytes 4. The gene is also upregulated in stress-responsive fibroblasts deficient for NOX4 5, suggesting broader roles in cellular stress adaptation beyond canonical starvation responses.