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SLFN11 governs DNA damage response during replication stress distinct from canonical routes, supports antiviral defense, and acts as a biomarker for predicting DNA-damaging agent efficacy and prognosis across 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[https://doi.org/10.1007/s10238-025-01776-y](https://doi.org/10.1007/s10238-025-01776-y)  \nSLFN11, far from being limited to responding to cancer DNA damage  \nHao Xiao1,2,3 · Zeping Han1,2,3 · Yingkai Tang4 · Xukang Gao1,2,3 · Min Xu1,2,3 · Shuangjian Qiu1,2,3 · Ning Ren1,2,3 · Yong Yi1,2,3 · Chenhao Zhou1,2,3  \nReceived: 5 May 2025 / Accepted: 15 June 2025 / Published online: 26 August 2025 © The Author(s) 2025  \nAbstract  \nSLFN11, a member of the evolutionarily conserved SLFN gene family, is an interferon-stimulated early response gene. This review comprehensively explores its multifaceted roles. Structurally, its three distinct domains endow it with diverse functions. Epigenetic modifications, post-translational alterations, and multiple signaling pathways intricately regulate SLFN11 expression and activity. In terms of functions, it plays crucial roles in the DNA damage response during replication stress, distinct from traditional pathways. It also serves as a protector in the antiviral response and a valuable biomarker for predicting the efficacy of DNA-damaging agents and patient prognosis in various cancers. Beyond these, SLFN11 has non-canonical functions, including immune regulation, modulation of oncological behaviors, involvement in apoptosis, protection against proteotoxic stress, and association with Fanconi anemia. Looking ahead, SLFN11 holds great promise as a biomarker for personalized medicine, but challenges like developing accurate detection methods remain. In immunotherapy, understanding its dynamic changes is essential for optimizing treatment. Strategies to overcome SLFN11-low expression, such as epigenetic modulation, also need further investigation, which may open new avenues for disease treatment.  \nKeywords Schlafen 11 · DNA damage response · Epigenetic modification · Antiviral function · Biomarker · Immune regulation · Oncological behavior  \nAbbreviations  \n(-)ssRNA Negative-sense single-stranded RNA  \n( +)ssRNA Positive-sense single-stranded RNA  \nAFP Alpha-fetoprotein  \nHao Xiao, Zeping Han and Yingkai Tang have contributed equally to this work.  \n* Yong Yi [yi.yong@zs-hospital.sh.cn](yi.yong@zs-hospital.sh.cn)  \n* Chenhao Zhou [zhouchenhao@fudan.edu.cn](zhouchenhao@fudan.edu.cn)  \n1 Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of China  \n2 Liver Cancer Institute, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of China  \n3 Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Ministry of Education, Shanghai 200032, People’s Republic of China  \n4 The Second Clinical Medical School of Nanjing Medical University, Nanjing 210029, Jiangsu, People’s Republic of China  \nAP-1  \nATM  \nATR  \nBCLC  \nBER  \nccRCC  \nCDK/DDK  \nCDT1  \nCHK1  \nCRC  \nCRL4  \nCRP  \nCRPC  \nCTCs  \nDDAs  \nDDB1  \nDDR  \nDENV  \neIF2a  \nER  \nERK  \nActivator protein-1  \nAtaxia telangiectasia mutated  \nAtaxia telangiectasia and Rad3-related protein kinase  \nBarcelona clinic liver cancer Base excision repair  \nClear cell renal cell carcinoma Cyclin-dependent and Dbf4-dependent kinases  \nReplication factor 1  \nCheckpoint kinase 1  \nColorectal cancer  \nCullin4-RING E3 ubiquitin ligase C-reactive protein  \nCastration-resistant prostate cancer Circulating tumor cells  \nDNA-damaging agents  \nDamage-specific DNA binding protein 1 DNA damage response  \nDengue virus  \nEukaryotic translation initiation factor 2A Endoplasmic reticulum  \nExtracellular signal-regulated kinase  \nETS  \nEZH2  \nFA  \nFLI-1  \nGC  \nGCBs  \nGCN2  \nGOF  \nH3K27me3  \nHCC  \nHCMV  \nHGSOC  \nHIV-1  \nHR  \nIAV  \nID  \nIEGs  \nIHC  \nIRF3  \nISGs  \nISR  \nJNK  \nMAP2K4  \nMAPK  \nMMR  \nMpBC  \nMSI  \nNHEJ  \nNLR  \nOS  \nPAMPs  \nPARP  \nPBD  \nPCNA  \nPFV  \nPPP1CC  \nRFS  \nRNase  \nRNR  \nRPA  \nRPS4X  \nSCLC  \nSF1  \nSLFN  \nssDNA  \nTNBC  \nTOP1  \nTROP2  \nTSP1  \nTYK2  \nUPR  \nWNV  \nE26 transformation-specific Enha","cbCaifwoOcQLQL7p","https://ap.wps.com/l/cbCaifwoOcQLQL7p","pdf",4000748,"English","# Abstract\n## Molecular regulation and structure\n## Roles in DNA damage response and antiviral defense\n## Biomarker potential and clinical challenges","[{\"question\":\"What regulates SLFN11 expression and activity?\",\"answer\":\"SLFN11 expression and activity are regulated by epigenetic modifications, post-translational alterations, and multiple signaling pathways.\"},{\"question\":\"How does SLFN11 contribute to the DNA damage response during replication stress?\",\"answer\":\"It plays crucial roles in the DNA damage response during replication stress, distinct from traditional pathways mentioned in the review.\"},{\"question\":\"Why is SLFN11 important for cancer treatment and prognosis?\",\"answer\":\"SLFN11 serves as a biomarker for predicting the efficacy of DNA-damaging agents and patient prognosis in various cancers, and immunotherapy may require monitoring its dynamic changes.\"}]","SLFN11 - far from being limited to responding to cancer DNA damage | PDF",1790200133,48]