Targeting NAT10 with Remodelin in cancer drug resistance: mechanisms, preclinical evidence, and combination strategies.

Drug resistance remains a major challenge in cancer therapy and limits the efficacy of chemotherapy, targeted therapy, and immunotherapy. Recent studies highlight RNA epitranscriptomic regulation, especially N4-acetylcytidine (ac4C), as an important mechanism in tumor adaptation. NAT10, the main enzyme that catalyzes ac4C formation, regulates RNA stability and translation. It plays key roles in cancer stemness, DNA repair, metabolic reprogramming, EMT, and immune regulation. Therefore, NAT10 has emerged as an important regulator of drug resistance in multiple cancer types. Mechanistically, NAT10 stabilizes key transcripts involved in DNA damage repair, metabolism, stemness, and EMT, thereby promoting tumor cell survival. It also enhances DNA repair by regulating DNA:RNA hybrid stability and homologous recombination, which reduces the effectiveness of DNA-damaging therapies. As a result, NAT10 contributes to resistance against cisplatin and other platinum drugs, doxorubicin, EGFR-TKIs, PARP inhibitors, and sorafenib. These resistance programs converge on a shared adaptive network involving DNA repair activation, metabolic rewiring, stemness maintenance, and immune escape. Remodelin is a small-molecule inhibitor of NAT10. It blocks ac4C modification and reverses drug resistance through multiple mechanisms. These include inhibition of DNA repair, suppression of metabolic adaptation, reversal of EMT, and improvement of the immune microenvironment. In preclinical models, Remodelin enhances the efficacy of chemotherapy, targeted therapy, and immunotherapy. However, clinical translation remains limited by issues such as off-target effects, toxicity, mechanistic complexity, and feedback regulation. Future work should focus on developing more selective NAT10 inhibitors, optimizing combination therapies, and identifying predictive biomarkers. Overall, NAT10 represents a potentially actionable regulator of cancer therapy resistance in selected tumor contexts, while Remodelin remains a useful preclinical tool for exploring NAT10-targeted strategies. Further validation is required before NAT10 inhibition can be considered a clinically applicable approach.