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However, their highly dynamic and context-dependent nature poses significant challenges to traditional general network models in capturing their true biological significance. Here, we introduce the formation of context-specific PPI networks, emphasizing the importance of the biological context in which PPIs occur. We systematically compare traditional experimental methods, mass spectrometry (MS)-based high-throughput technologies, and structure- and biophysics-based approaches across six dimensions. Although these experimental methods have generated valuable data resources, they still suffer from limitations, including low capture efficiency for transient or weak interactions and a lack of gold-standard datasets with specific biological contexts. Furthermore, we review recent advances in context-specific PPI inference strategies centered on omics data integration, and highlight the emerging potential of large cellular models (LCMs) to generate context-aware representations that support the construction of context-specific PPI networks. In the future, comprehensive context-specific PPI networks are expected to more accurately reflect the biological system, thereby enabling deeper mechanistic insights, improving disease interpretation, and accelerating the discovery of therapeutic targets.<\/jats:p>","DOI":"10.1093\/bib\/bbag004","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T12:29:53Z","timestamp":1767702593000},"source":"Crossref","is-referenced-by-count":0,"title":["Strategies for constructing context-specific protein\u2013protein interaction networks"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8447-3326","authenticated-orcid":false,"given":"Shiyan","family":"Nie","sequence":"first","affiliation":[{"name":"Hengyang Medical School, University of South China , 28 Changsheng West Road, Zhengxiang District, Hengyang, Hunan, 421001, \u00a0","place":["China"]},{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Academy of Military Medical Sciences , 38 Life Science Park, Changping District, Beijing 102206 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6872-0367","authenticated-orcid":false,"given":"Xiangren","family":"Kong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Academy of Military Medical Sciences , 38 Life Science Park, Changping District, Beijing 102206 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8680-0468","authenticated-orcid":false,"given":"Dong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Academy of Military Medical Sciences , 38 Life Science Park, Changping District, Beijing 102206 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