DHRS9 generates crotonyl-CoA from butyryl-CoA to epigenetically regulate STING transcription and potentiate immune activation.

The stimulator of interferon genes (STING) pathway is a cornerstone of innate immunity and a promising therapeutic target for autoimmune diseases, inflammation, and cancer treatment. Lysine crotonylation, a recently discovered post-translational modification, regulates various cellular processes; however, its role in STING activation remains unclear. Here, we identified dehydrogenase/reductase (SDR family) member 9 (DHRS9) as a critical metabolic regulator of the STING signaling pathway. DHRS9 deficiency impaired activation of the cGAS-STING pathway, suppressed antiviral immunity against HSV-1, and exacerbated viral replication. Mechanistically, DHRS9 converts butyryl-CoA into crotonyl-CoA, thereby enhancing histone crotonylation (H3K14cr and H3K18cr) at the STING promoter to drive its transcription. AAV-mediated DHRS9 delivery significantly enhances antiviral and antitumor immunity, demonstrating its robust therapeutic potential. This study reveals a metabolic-epigenetic axis that regulates STING expression, offering new therapeutic strategies for immune-related diseases.