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To address this gap, we established human 3D airway organoids that recapitulate native epithelial architecture and function to assess the respiratory toxicity of 10 PFAS compounds. At 0.1 \u03bcM, a concentration relevant to high-exposure, PFASs induced a cascade of effects, including mitochondrial dysfunction, barrier disruption, and inflammation. These events converged on epithelial differentiation imbalance, characterized by a 21\u201366% reduction in ciliated cells marker FOXJ1 and a 1.2\u20132.3-fold upregulation of goblet cells marker MUC5AC. Multiend point Toxicological Priority Index ranking revealed that emerging substitutes, particularly sodium p-perfluorinated noneoxybenzenesulfonate (OBS) and fluorotelomer alcohols (FTOHs), exhibited higher toxicity potency than legacy compounds. In vivo validation confirmed perfluorooctanesulfonic acid (PFOS)-induced airway obstruction and mucus hypersecretion, supporting the in vivo relevance of organoid-derived airway injury phenotypes. Single-cell transcriptomics implicated Notch-related signaling in PFOS-associated differentiation disturbance, supported by inhibitor intervention. These findings provide functional and mechanistic evidence relevant to obstructive airway disease; establish an adverse outcome pathway for PFASs\u2019 respiratory toxicity; and provide a sensitive, predictive platform for hazard identification and regulatory prioritization of emerging PFASs.<\/jats:p>","DOI":"10.1021\/acs.est.6c04546","type":"journal-article","created":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T17:53:56Z","timestamp":1788112436000},"page":"24566-24579","source":"Crossref","is-referenced-by-count":0,"title":["PFASs Disrupt Airway\nEpithelial Homeostasis in Human\nOrganoids: Evidence Relevant to Obstructive Airway Disease"],"prefix":"10.1021","volume":"60","author":[{"given":"Yuxin","family":"Niu","sequence":"first","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sirui","family":"Zhu","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueming","family":"Lang","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cui","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liguo","family":"Xing","sequence":"additional","affiliation":[{"name":"Shenyang SYRICI Testing , ,","place":["Shenyang, China, 110021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shenyang SYRICI Testing , ,","place":["Shenyang, China, 110021"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8920-1172","authenticated-orcid":true,"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"issue":"52","key":"2026090809070972200_cit1","doi-asserted-by":"publisher","first-page":"78698","DOI":"10.1007\/s11356-022-20829-3","article-title":"Bioavailability\nof inhaled or ingested PFOA adsorbed to house dust","volume":"29","author":"Gustafsson","year":"2022","journal-title":"Environ. 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