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Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the posttranscriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that ~70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs, enriched in suboptimal codons and bearing short poly(A) tails under normal diet, becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3\u2032 UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.<\/jats:p>","DOI":"10.1126\/sciadv.aea4125","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T17:58:57Z","timestamp":1775239137000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Posttranscriptional reprogramming controls MASLD progression through chronic ER stress adaptation"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1059-3546","authenticated-orcid":true,"given":"Eulalia","family":"Belloc","sequence":"first","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6494-2287","authenticated-orcid":true,"given":"Vittorio","family":"Calderone","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7038-0753","authenticated-orcid":true,"given":"Salvador","family":"Naranjo-Suarez","sequence":"additional","affiliation":[{"name":"FRCB-IDIBAPS Biomedical Research Institute, 08036 Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9076-4025","authenticated-orcid":true,"given":"Lidia","family":"Mateo","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4193-7890","authenticated-orcid":true,"given":"Judit","family":"Martin","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florencia","family":"Malizia","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2496-8783","authenticated-orcid":true,"given":"Annarita","family":"Sibilio","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7280-1884","authenticated-orcid":true,"given":"Veronica","family":"Chanes","sequence":"additional","affiliation":[{"name":"Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2135-4935","authenticated-orcid":true,"given":"Marta","family":"Ramirez-Pedraza","sequence":"additional","affiliation":[{"name":"FRCB-IDIBAPS Biomedical Research Institute, 08036 Barcelona, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8653-1819","authenticated-orcid":true,"given":"M. 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