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Epithelial-mesenchymal transition (EMT) significantly contributes to BTC metastasis, yet the critical regulators and underlying molecular mechanisms of EMT remain poorly unclear. In our study, we conducted an integrative analysis of single-cell RNA sequencing (scRNA-seq) data from 47 BTC samples, identifying two EMT-enriched epithelial subpopulations and a BTC specific EMT gene set. Using the EMT gene set, we classified BTC patients and noticed that those with elevated EMT scores had worse prognoses. Additionally, multi-omics analyses identified PMEPA1 as a pivotal EMT regulator, with its high expression levels correlating with adverse prognosis and distant metastasis. Functional assays revealed that PMEPA1 knockdown inhibits, while its overexpression promotes EMT progression by modulating Hippo-YAP signaling, specifically YAP1 nuclear localization. Moreover, we forecast and validated topoisomerase inhibitor SN-38 as a potential EMT-targeting agent. SN-38 effectively inhibited BTC cell migration and metastasis in vivo, likely by attenuating the transcriptional activity of PMEPA1 and its upstream regulator FOS. Overall, this research elucidates EMT-related molecular features in BTC, reveals PMEPA1 as a critical EMT driver via the Hippo-YAP1 pathway, and proposes SN-38 as a promising therapeutic candidate, offering new insights into BTC metastasis and precision therapy.<\/jats:p>","DOI":"10.1038\/s41419-026-08684-3","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T05:36:39Z","timestamp":1775194599000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PMEPA1 modulates YAP1 nuclear translocation to disrupt EMT subtypes and promote metastasis in Biliary tract cancer"],"prefix":"10.1038","volume":"17","author":[{"given":"Wenwen","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6830-8568","authenticated-orcid":false,"given":"Chaoqun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinxing","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruitang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaiwen","family":"Sheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haoqiang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"ZhaoXiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongguang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4102-2295","authenticated-orcid":false,"given":"Dianhao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6298-6192","authenticated-orcid":false,"given":"Shuhong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,3]]},"reference":[{"key":"8684_CR1","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/S0140-6736(21)00153-7","volume":"397","author":"JW Valle","year":"2021","unstructured":"Valle JW, Kelley RK, Nervi B, Oh D-Y, Zhu AX. 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