Targeting Ash1L-STING Axis Restores NK Cell Function and Ameliorates Immune-Mediated Bone Marrow Failure Diseases.

Aplastic anemia (AA) is an immune-mediated bone marrow failure (BMF) syndrome characterized by pancytopenia and bone marrow hypocellularity. While natural killer (NK) cell dysfunction contributes to AA pathogenesis, the epigenetic mechanisms linking genomic instability to inflammatory hyperactivation remain poorly defined. Here, we identify the histone methyltransferase Ash1L as a critical regulator of NK cell homeostasis in AA. Ash1L expression was markedly reduced in NK cells from AA patients and correlated with disease severity and elevated proinflammatory cytokines. Ash1L knockdown reduced NK cell viability, induced apoptosis and G1 cell-cycle arrest, and enhanced secretion of IL-6 and TNF-α. Mechanistically, Ash1L deficiency resulted in reduced H3K4 and H3K36 methylation, impairing activation of the ATM-CHK2-p53 signaling pathway, resulting in persistent γH2AX foci accumulation and aberrant activation of the cGAS-STING signaling pathway. Treatment with the natural compound Andrographolide (Andro) suppressed STING signaling, enhanced DNA damage repair efficiency, and partially restored NK cell function. In an immune-mediated BMF mouse model, Andro attenuated inflammatory responses, restored Ash1L expression in NK cells, inhibited STING pathway activation, and improved hematopoiesis. Collectively, these findings suggest that Ash1L acts as an epigenetic safeguard of genomic stability and inflammatory restraint in NK cells and highlight Andro as a potential therapeutic agent for AA and related immune-mediated BMF disorders.