tRF-1432 orchestrates RBMS1-IMPDH2 regulatory control to drive purine-dependent chemoresistance in breast cancer.

Chemoresistance remains a major obstacle to effective breast cancer therapy and is driven in part by metabolic reprogramming and dysregulated RNA-mediated signaling. Although tRNA-derived fragments (tRFs) have emerged as important regulators of cellular stress responses, their roles in drug resistance remain incompletely understood. Here, using high-throughput sequencing, we identified tRF-1432 as a markedly upregulated tRF in chemoresistant breast cancer tissues and cell lines, which was further validated in clinical specimens. Functional assays and syngeneic tumor models demonstrated that tRF-1432 enhances resistance to adriamycin by promoting tumor cell survival and suppressing apoptosis under chemotherapeutic stress. Mechanistically, tRF-1432 is a 5'-tRNA^Val-CAC-derived fragment generated by angiogenin cleavage and directly interacts with the RNA-binding protein RBMS1. This interaction attenuates RBMS1-mediated destabilization of IMPDH2 mRNA, leading to increased IMPDH2 expression. As a result, purine metabolic reprogramming is enhanced, intracellular GTP levels are elevated, and proliferative and survival signaling is sustained in the presence of chemotherapy. Importantly, pharmacological inhibition of IMPDH2 using mycophenolic acid (MPA), an FDA-approved drug, effectively reversed chemoresistance both in vitro and in vivo. Collectively, our findings establish a previously unrecognized tRF-1432/RBMS1/IMPDH2 regulatory axis that drives metabolic adaptation and chemoresistance in breast cancer, highlighting this pathway as a potential therapeutic target for overcoming drug resistance.