Targeting NAT10 suppresses TFH responses and alleviates allergic asthma via an ac4C-TOX2 axis

Cheng, Z.-L.; Lin, Z.; Ren, Y.; Zhou, Y.; Yang, Y.; Yang, Z.; Wang, K.; Li, X.; Zheng, Y.; Liu, C.; Wang, X.; Wu, D.

doi:10.64898/2026.07.21.739954

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bioRxiv · 10.64898/2026.07.21.739954

Targeting NAT10 suppresses TFH responses and alleviates allergic asthma via an ac4C-TOX2 axis

Cheng, Z.-L.·Lin, Z.·Ren, Y.·Zhou, Y.·Yang, Y.·Yang, Z.·Wang, K.·Li, X.·Zheng, Y.·Liu, C.·Wang, X.·Wu, D.

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Abstract

Chemical modifications of RNA, such as N4-acetylcytidine (acC), fine-tune gene expression, but their roles in cell fate determination within the immune system remain poorly understood. Here, we identify the RNA cytidine acetyltransferase NAT10 as a pivotal regulator of T follicular helper (TFH) cell differentiation and the germinal centre response. T cell-specific ablation of Nat10 in mice severely impaired TFH cell development, germinal centre formation, and antibody production following viral infection. Integrated epitranscriptomic and transcriptional profiling revealed that NAT10 deposits acC modifications on a cohort of mRNAs critical for immune function. We pinpointed the transcription factor TOX2 as a key downstream target, showing that acC modification within its mRNA coding sequence enhances both transcript stability and translation efficiency, thereby promoting TOX2 protein expression. Enforced TOX2 expression fully rescued the TFH differentiation defect in NAT10-deficient cells. This NAT10-acC-TOX2 axis is conserved in humans, where its activity correlates with the magnitude of vaccine-elicited TFH responses. Furthermore, we identified R428 as a potent NAT10 inhibitor and demonstrated that its administration could suppress pathogenic TFH responses and alleviate symptoms in a mouse model of allergic asthma. Our work elucidates a central epitranscriptomic mechanism controlling T helper cell fate and humoral immunity, and nominates NAT10 as a potential therapeutic target for TFH-driven diseases.

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Cheng, Z.-L., Lin, Z., Ren, Y., Zhou, Y., Yang, Y., Yang, Z., Wang, K., Li, X., Zheng, Y., Liu, C., Wang, X., Wu, D.. 2026-07-25. Targeting NAT10 suppresses TFH responses and alleviates allergic asthma via an ac4C-TOX2 axis. https://doi.org/10.64898/2026.07.21.739954

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