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Here, we applied an ultrahigh-throughput affinity selection\u2013mass spectrometry (AS\u2013MS) platform to systematically identify protein targets of prioritized chemical contaminants. After benchmarking the platform, we screened 50 human proteins against 481 prioritized chemicals, including 446 ToxCast chemicals and 35 per- and polyfluoroalkyl substances (PFAS). Among 24,050 interactions assessed, we discovered 35 interactions involving 13 proteins, with fatty acid\u2013binding proteins (FABPs) emerging as the most ligandable protein family. Given this, we selected FABPs for further validation, which revealed a distinct PFAS binding pattern: legacy PFAS selectively bound to FABP1, whereas replacement compounds, perfluoroether carboxylic acids, unexpectedly interacted with all FABPs. X-ray crystallography further revealed that the ether group enhances the molecular flexibility of alternative PFAS to accommodate the binding pockets of FABPs. Our findings demonstrate that AS\u2013MS is a robust platform for the discovery of protein targets beyond the scope of ToxCast and highlight the broader protein-binding spectrum of alternative PFAS as potential regrettable substitutes.<\/jats:p>","DOI":"10.1073\/pnas.2515940123","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T18:11:48Z","timestamp":1780683108000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["High-throughput protein target mapping enables accelerated bioactivity discovery for ToxCast and PFAS compounds"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6951-9298","authenticated-orcid":false,"given":"Diwen","family":"Yang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03dbr7087","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physical and Environmental Sciences, University of Toronto 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