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Here, we propose the Dual\u2010branch Molecular Property Encapsulation (DMPE) framework. Its core component, the Refined Interactive Graph Attention Framework (RIGAF), captures both intramolecular topology and intermolecular structural similarity within the broader chemical space. Subsequently, a Kolmogorov\u2010Arnold Network (KAN)\u2010based Embedding and Fusion (KAEF) module uses spline\u2010based transformations to integrate these graph features with complementary molecular fingerprints, enhancing model interpretability while maintaining strong generalizability. DMPE performs competitively, with superior ROC\u2010AUC scores on scaffold\u2010based BBBP (0.927) and multi\u2010label SIDER (0.691) benchmarks, alongside promising accuracy across nine of 14 breast cancer cell lines. Key components of our architecture are validated through ablation studies. Model reliability is bolstered by Monte Carlo dropout for uncertainty estimation, which also serves as an ensemble strategy to enhance accuracy. The framework was applied to the identification of potential hematopoietic progenitor kinase 1 (HPK1) inhibitors for hepatocellular carcinoma.<\/jats:p>","DOI":"10.1002\/jcc.70273","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T14:02:36Z","timestamp":1763128956000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DMPE: A Dual\u2010Branch Molecular Property Encapsulation Framework With Kolmogorov\u2010Arnold Networks"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7453-9330","authenticated-orcid":false,"given":"Lihui","family":"Duo","sequence":"first","affiliation":[{"name":"Department of Chemical and Environmental Engineering University of Nottingham Ningbo China  Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4301-2496","authenticated-orcid":false,"given":"Bencan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Chemical and Environmental Engineering University of Nottingham Ningbo China  Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2726-0983","authenticated-orcid":false,"given":"Jonathan D.","family":"Hirst","sequence":"additional","affiliation":[{"name":"School of Chemistry University of Nottingham  Nottingham UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0207-4500","authenticated-orcid":false,"given":"Hua","family":"Xie","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Materia Medica  Pudong Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4619-6590","authenticated-orcid":false,"given":"Jianfeng","family":"Ren","sequence":"additional","affiliation":[{"name":"School of Computer Science University of Nottingham Ningbo China  Ningbo China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.0c00699"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1039\/C7SC02664A"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41524-023-01194-2"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-024-01679-1"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.8b00728"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13321-020-00460-5"},{"key":"e_1_2_10_8_1","first-page":"1983","volume-title":"Proc. 48th IEEE Intl. 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