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Dysregulation of PPIs underlies a spectrum of diseases, including cancer, neurodegenerative disorders, and autoimmune conditions, highlighting the imperative of investigating these interactions for therapeutic advancements. This review delves into the realm of mass spectrometry-based techniques for elucidating PPIs and their profound implications in biological research. Mass spectrometry in the PPI research field not only facilitates the evaluation of protein\u2013protein interaction modulators but also discovers unclear molecular mechanisms and sheds light on both on- and off-target effects, thus aiding in drug development. Our discussion navigates through six pivotal techniques: affinity purification mass spectrometry (AP-MS), proximity labeling mass spectrometry (PL-MS), cross-linking mass spectrometry (XL-MS), size exclusion chromatography coupled with mass spectrometry (SEC-MS), limited proteolysis-coupled mass spectrometry (LiP-MS), and thermal proteome profiling (TPP).<\/jats:p>","DOI":"10.1007\/s42485-024-00156-6","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T06:02:04Z","timestamp":1719554524000},"page":"545-559","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Progress in mass spectrometry approaches to profiling protein\u2013protein interactions in the studies of the innate immune system"],"prefix":"10.1007","volume":"15","author":[{"given":"Doeun","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Nita-Lazar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,28]]},"reference":[{"issue":"2","key":"156_CR1","doi-asserted-by":"publisher","first-page":"97","DOI":"10.4067\/s0716-97602007000200001","volume":"40","author":"SA Arancibia","year":"2007","unstructured":"Arancibia SA, Beltran CJ, Aguirre IM, Silva P, Peralta AL, Malinarich F, Hermoso MA (2007) Toll-like receptors are key participants in innate immune responses. 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