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The cellular crosstalk driving periductal fibrosis remains poorly defined. This study applied a multi-omics approach integrating MERSCOPE spatial transcriptomics, bulk RNA-seq, and SomaScan proteomics to characterize fibrotic periductal regions and their cell\u2013cell communications. Macrophages (MP) expressing moderate-to-high CD163 were found co-localized with cholangiocytes, T cells, and collagen-producing hepatic stellate cells (HSC). Cell niche analysis identified periductal regions with elevated fibrotic signals, in which cell\u2013cell communication analysis revealed MP\u2013HSC interactions involving 17 fibrotic driver genes in MP (e.g., IFNGR1, CSF1R, CD163) and six fibrotic effector genes in HSC (e.g., COL1A2, VCAN, MMP2). In validation analyses, bulk RNA-seq data showed higher driver and effector gene scores in PSC with established fibrosis compared to early-stage PSC and autoimmune hepatitis (AIH). Plasma proteins encoded by MP driver genes were elevated in autoimmune liver disease (AILD) and in patients with elevated (\u22653.29 kPa) liver stiffness on MR elastography. These findings suggest that macrophages engage in localized crosstalk with HSC, activating fibrotic gene programs and contributing to periductal fibrosis in PSC, thereby identifying potential molecular targets for therapeutic intervention.<\/jats:p>","DOI":"10.1101\/2025.08.14.670195","type":"posted-content","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T17:10:12Z","timestamp":1755796212000},"source":"Crossref","is-referenced-by-count":0,"title":["Macrophages drive a fibrogenic gene program of periductal fibroblasts in pediatric primary sclerosing cholangitis"],"prefix":"10.64898","author":[{"given":"Yunguan","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Adeleke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangfei","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika Yang","family":"von Hofe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manavi","family":"Singh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astha","family":"Malik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramesh","family":"Kudira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cyd","family":"Castro-Rojas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liva","family":"Pfuhler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mosab","family":"Alquraish","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pamela","family":"Sylvestre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan R.","family":"Dillman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1431-4054","authenticated-orcid":false,"given":"Andrew T.","family":"Trout","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Miraldi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander G.","family":"Miethke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025082307001562000_2025.08.14.670195v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2616"},{"key":"2025082307001562000_2025.08.14.670195v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29204"},{"issue":"1","key":"2025082307001562000_2025.08.14.670195v1.3","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4254\/wjh.v11.i1.19","article-title":"Treatment of primary sclerosing cholangitis in children","volume":"11","year":"2019","journal-title":"World J Hepatol"},{"issue":"3","key":"2025082307001562000_2025.08.14.670195v1.4","doi-asserted-by":"crossref","first-page":"e0265418","DOI":"10.1371\/journal.pone.0265418","article-title":"Periductal bile acid exposure causes cholangiocyte injury and fibrosis","volume":"17","year":"2022","journal-title":"PLoS One"},{"issue":"4","key":"2025082307001562000_2025.08.14.670195v1.5","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.jcmgh.2024.01.005","article-title":"Cellular Interactions and Crosstalk Facilitating Biliary Fibrosis in Cholestasis","volume":"17","year":"2024","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"2025082307001562000_2025.08.14.670195v1.6","doi-asserted-by":"crossref","unstructured":"Cadamuro M , Girardi N , Gores GJ , Strazzabosco M , and Fabris L . 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