Peptide-based therapeutics hold great promise for the treatment of various diseases; however, their clinical application is often hindered by toxicity challenges. The accurate prediction of peptide toxicity is crucial for designing safe peptide-based therapeutics. While traditional experimental approaches are time-consuming and expensive, computational methods have emerged as viable alternatives, including similarity-based and machine learning (ML)-/deep learning (DL)-based methods. However, existing methods often struggle with robustness and generalizability. To address these challenges, we propose HyPepTox-Fuse, a novel framework that fuses protein language model (PLM)-based embeddings with conventional descriptors. HyPepTox-Fuse integrates ensemble PLM-based embeddings to achieve richer peptide representations by leveraging a cross-modal multi-head attention mechanism and Transformer architecture. A robust feature ranking and selection pipeline further refines conventional descriptors, thus enhancing prediction performance. Our framework outperforms state-of-the-art methods in cross-validation and independent evaluations, offering a scalable and reliable tool for peptide toxicity prediction. Moreover, we conducted a case study to validate the robustness and generalizability of HyPepTox-Fuse, highlighting its effectiveness in enhancing model performance. Furthermore, the HyPepTox-Fuse server is freely accessible at https://balalab-skku.org/HyPepTox-Fuse/ and the source code is publicly available at https://github.com/cbbl-skku-org/HyPepTox-Fuse/. The study thus presents an intuitive platform for predicting peptide toxicity and supports reproducibility through openly available datasets.

Peptide-based therapeutics hold great promise for the treatment of various diseases;however,their clinical application is often hindered by toxicity challenges.The accurate prediction of peptide toxicity is crucial for designing safe peptide-based therapeutics.While traditional experimental approaches are time-consuming and expensive,computational methods have emerged as viable alternatives,including similarity-based and machine learning(ML)-/deep learning(DL)-based methods.However,existing methods often struggle with robustness and generalizability.To address these challenges,we propose HyPepTox-Fuse,a novel framework that fuses protein language model(PLM)-based embeddings with conventional descriptors.HyPepTox-Fuse integrates ensemble PLM-based embeddings to achieve richer peptide representations by leveraging a cross-modal multi-head attention mechanism and Transformer architecture.A robust feature ranking and selection pipeline further refines conventional descriptors,thus enhancing prediction performance.Our framework outperforms state-of-the-art methods in cross-validation and independent evaluations,offering a scalable and reliable tool for peptide toxicity pre-diction.Moreover,we conducted a case study to validate the robustness and generalizability of HyPepTox-Fuse,highlighting its effectiveness in enhancing model performance.Furthermore,the HyPepTox-Fuse server is freely accessible at https://balalab-skku.org/HyPepTox-Fuse/and the source code is publicly available at https://github.com/cbbl-skku-org/HyPepTox-Fuse/.The study thus presents an intuitive platform for predicting peptide toxicity and supports reproducibility through openly available datasets.