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Here we report that aged MuSCs can autonomously instruct fibro-adipogenic progenitors (FAPs) to proliferate and acquire a fibrogenic phenotype, independent of other cell types. Both the polycomb-deficient\n                    <jats:italic>Ezh2<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mouse model and aged mice exhibited defective regeneration, FAP expansion, fibrosis and elevated secretion of interleukin 6 (IL-6) and secreted phosphoprotein 1 (Spp1; osteopontin) by MuSCs. In aged MuSCs, reduction of the histone H3K27me3 repressive mark at the\n                    <jats:italic>Nfbk1<\/jats:italic>\n                    gene correlated with its increased expression and enhanced chromatin recruitment to the\n                    <jats:italic>IL6<\/jats:italic>\n                    and\n                    <jats:italic>Spp1<\/jats:italic>\n                    genes, leading to their activation. Pharmacological inhibition of IL-6 and Spp1 signaling in co-culture systems or in aged mice reduced FAP proliferation and muscle fibrosis. These findings indicate that epigenetic dysregulation of aged MuSCs contributes to aged-related muscle fibrosis.\n                  <\/jats:p>","DOI":"10.1038\/s43587-025-01002-0","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T10:49:05Z","timestamp":1761734945000},"page":"2399-2416","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Epigenetic dysregulation in aged muscle stem cells drives mesenchymal progenitor expansion via IL-6 and Spp1 signaling"],"prefix":"10.1038","volume":"5","author":[{"given":"Giulia","family":"Riparini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0344-3637","authenticated-orcid":false,"given":"Morgan","family":"Mackenzie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faiza","family":"Naz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9065-4574","authenticated-orcid":false,"given":"Kan","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshu","family":"Deewan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany","family":"Dulek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamima","family":"Islam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Dae","family":"Ko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanxia L.","family":"Tsai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9084-6736","authenticated-orcid":false,"given":"Massimo","family":"Gadina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Dell\u2019Orso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-3675","authenticated-orcid":false,"given":"Vittorio","family":"Sartorelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,29]]},"reference":[{"key":"1002_CR1","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms8087","volume":"6","author":"AC Keefe","year":"2015","unstructured":"Keefe, A. 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