Prothymosin alpha (PTMA) is a highly conserved, intrinsically disordered nuclear protein with multifaceted roles in cellular homeostasis and immunity. Primary function: PTMA acts as a linker histone chaperone facilitating chr2 remodeling and serves as a critical regulator of cell proliferation and stress responses 1. Mechanism: PTMA promotes linker histone H1.0 release from damaged chr2, enabling efficient recruitment of DNA repair proteins including PARP1 1. In cardiomyocytes, PTMA enhances STAT3 acetylation by inhibiting MBD3 deacetylation activity within the NuRD complex, driving proliferation and cardiac repair 2. In CD8 T cells, PTMA is controlled by TCF1 and preserves mitochondrial DNA integrity through TFAM interaction, sustaining oxidative phosphorylation and antitumor immunity 3. Disease relevance: PTMA upregulation moderates inflammatory responses and prevents osteoclastogenesis in apical periodontitis 4. High PTMA expression associates with cancer stemness and immunotherapy resistance 5. Clinical significance: PTMA overexpression extends the neonatal cardiac proliferative window and shows therapeutic promise for ischemic myocardial injury 2. PTMA deletion impairs CD8 T cell persistence and abolishes PD-1 blockade efficacy 3. Topical and systemic PTMA administration alleviates periapical lesions 4.