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DHRS9 generates crotonyl-CoA from butyryl-CoA to epigenetically regulate STING transcription and potentiate immune activation
Zhang Yuling, Qin Fei, Zhang Jiajia, Bai Xuemei, Yuan Jiahua, Cao Nan, Dong Na, Zhou Min, He Ziye, Li Xiaoxiao, Wang Huanming, Gao Chengjiang, Liu Bingyu
Journal：CELL DEATH AND DIFFERENTIATION
IF：13.6
DOI：10.1038/s41418-026-01819-1
PMID：
Published：2026-07-15
research field：
Abstract
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.
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