SLFN11 is a multifunctional protein that serves as a guardian of genome stability and antiviral defense. Its primary function involves inhibiting DNA replication under stress conditions, promoting cell death in response to DNA damage through multiple mechanisms 12. SLFN11 acts by blocking stressed replication forks and inducing ribosome stalling on rare UUA leucine codons, leading to translation inhibition and p53-independent apoptosis 1. Additionally, SLFN11 impairs ribosome biogenesis by inhibiting rRNA synthesis, preferentially depleting short-lived proteins like MCL1 to trigger apoptosis 2. The protein functions as an interferon-induced antiviral restriction factor with tRNA endoribonuclease activity, specifically targeting retroviruses and other viruses through codon-usage-dependent mechanisms. Clinically, SLFN11 expression serves as a predictive biomarker for chemotherapy response, particularly to topoisomerase inhibitors 34. In hepatocellular carcinoma, SLFN11 acts as a tumor suppressor by targeting RPS4X and inhibiting the mTOR pathway 5. Furthermore, SLFN11 regulates immune responses by modulating macrophage polarization and serves as a biomarker for immunotherapy response 6. Its frequent inactivation in chemotherapy-resistant tumors highlights its therapeutic significance 1.