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

Authors

Yuling Zhang, Fei Qin, Jiajia Zhang, Xuemei Bai, Jiahua Yuan, Nan Cao, Na Dong, Min Zhou, Ziye He, Xiaoxiao Li, Huanming Wang, Chengjiang Gao, Bingyu Liu

Published in

Cell death and differentiation. Jul 15, 2026. Epub Jul 15, 2026.

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.

PMID:
42457927
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.

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