Esophageal squamous cell carcinoma (ESCC) is a highly lethal cancer with limited therapeutic options and frequent relapse. RNA acetylation has emerged as a crucial regulator of tumor biology. In this study, we identify circTHBS1 as an oncogenic circRNA that promotes autophagy and drives ESCC progression. Mechanistically, circTHBS1 interacts with the N -acetyltransferase 10 (NAT10), preventing its ubiquitin-mediated proteasomal degradation and thereby increasing global N 4 -acetylcytidine (ac 4 C) modification. Rab8a is identified as a key ac 4 C target, where ac 4 C modification at a conserved CGCCAG motif within the coding sequence facilitates NAT10 binding and enhances translation. Disruption of this modification impairs Rab8a-driven autophagy and suppresses tumor progression. Collectively, our findings reveal a circTHBS1/NAT10-ac 4 C/Rab8a axis that reprograms translational control and autophagy, providing new mechanistic insights and potential therapeutic targets for ESCC. • circTHBS1 upregulation is related to progression and poor prognosis in ESCC. • circTHBS1 blocks NAT10 ubiquitination, promoting ac 4 C modification in ESCC. • circTHBS1-driven NAT10-ac 4 C modification enhances translation of target transcripts. • The circTHBS1/NAT10-ac 4 C/Rab8a axis enhances autophagy and drives tumor progression.
Xie et al. (Sun,) studied this question.