biostudies-literatureLi ZU.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesU.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)NIGMS NIH HHS891https://www.ebi.ac.uk/biostudies/studies/S-EPMC12830971biostudies-literatureUnknown17(1)Predicting changes in protein thermostability caused by amino acid substitutions is essential for understanding human diseases and engineering proteins for practical applications. While recent protein generative models demonstrate impressive zero-shot performance in predicting various protein properties without task-specific training, their strong unsupervised prediction ability remains underexploited to improve protein stability prediction. We present SPURS, a deep learning framework that rewires and integrates two complementary protein generative models-a protein language model and an inverse folding model-and reprograms this unified framework for stability prediction through supervised fine-tuning on mega-scale thermostability data. SPURS delivers accurate, efficient, and scalable stabiNature communicationsGeneralizable and scalable protein stability prediction with rewired protein generative models.PMC12830971R35GM150890R35 GM150890Li ZLuo YfalseGeneralizable and scalable protein stability prediction with rewired protein generative models.Predicting changes in protein thermostability caused by amino acid substitutions is essential for understanding human diseases and engineering proteins for practical applications. While recent protein generative models demonstrate impressive zero-shot performance in predicting various protein properties without task-specific training, their strong unsupervised prediction ability remains underexploited to improve protein stability prediction. We present SPURS, a deep learning framework that rewires and integrates two complementary protein generative models-a protein language model and an inverse folding model-and reprograms this unified framework for stability prediction through supervised fine-tuning on mega-scale thermostability data. SPURS delivers accurate, efficient, and scalable stabi2025-01-01T00:00:00Z2025 Dec2026-06-11T06:03:45.664Z2026-06-11T03:12:01.231ZS-EPMC128309714142222810.1038/s41467-025-67609-4