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We used a murine ischemia-reperfusion AKI model. Unbiased liver proteomics was performed at 24\u00a0h after reperfusion, and dysregulated pathways were identified by Gene Set Enrichment Analysis. Results were validated by Western blotting, qPCR, and immunohistochemistry. These findings were complemented by retrospective analysis of two intensive care unit (ICU) databases (the Medical Information Mart for Intensive Care IV [MIMIC-IV] and the eICU Collaborative Research Database [eICU-CRD]). AKI significantly increased serum ALT and AST and induced hepatic lipid accumulation. Proteomic analysis revealed that key lipogenic enzymes (SCD1, FASN, ACLY, ACACA) were uniformly suppressed rather than upregulated. ApoB and MTTP, proteins essential for very-low-density lipoprotein (VLDL) assembly, were significantly downregulated, while ApoE showed a concordant downward trend (adjusted p\u2009=\u20090.072). Plasma triglycerides were decreased while liver triglycerides were increased, consistent with impaired hepatic lipid export. As in renal tubular cells, AKI also disrupted ER protein folding homeostasis in the liver, triggering ER stress. This was evidenced by upregulated levels of the ER chaperone GRP78, increased XBP1 splicing indicative of UPR activation, and elevated expression of the ER stress-induced pro-apoptotic transcription factor CHOP, suggesting that prolonged ER stress may also promote hepatocyte cell death. TLR4\/MyD88 signaling was activated, yet inflammatory cytokines were paradoxically reduced, accompanied by Kupffer cell depletion (decreased F4\/80) and monocyte infiltration (increased CD68). In 6,996 propensity-matched ICU patients (MIMIC-IV), AKI independently increased the risk of clinically significant liver injury 4-fold (adjusted OR\u2009=\u20094.41). Analysis of 22,727 patients across 208 hospitals (eICU-CRD) identified a lipid dissociation pattern: elevated triglycerides alongside decreased total cholesterol, HDL, and LDL, with dose-dependent scaling across KDIGO stages. These data are consistent with ER stress-associated impairment of VLDL export contributing to AKI-induced hepatic steatosis. Clinical cohort analyses across two independent ICU databases identify a dual metabolic insult: enhanced peripheral lipid delivery compounds impaired hepatic export, amplifying hepatic lipid retention. ER stress and lipid export machinery represent potential therapeutic targets for AKI-associated liver injury.<\/jats:p>","DOI":"10.1038\/s41598-026-59445-3","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T21:07:35Z","timestamp":1782767255000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ER stress-mediated impairment of hepatic lipid export is associated with steatosis in AKI-induced remote liver injury"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3732-2737","authenticated-orcid":false,"given":"Minghua","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runze","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristof","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriame","family":"Melaika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas Eli","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Subramanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran","family":"Dhanireddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruisheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"59445_CR1","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1093\/ndt\/gfaa297","volume":"37","author":"A Bonavia","year":"2022","unstructured":"Bonavia, A. & Stiles, N. 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Theranostics 10, 10874\u201310891. https:\/\/doi.org\/10.7150\/thno.47037 (2020).","journal-title":"Theranostics"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-59445-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-59445-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-59445-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T22:42:35Z","timestamp":1790548955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-59445-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["59445"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-59445-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-9409706\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]},"assertion":[{"value":"14 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of South Florida, Morsani College of Medicine (protocol 12005R), and all methods were performed in accordance with the relevant guidelines and regulations, including the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The study is reported in accordance with the ARRIVE guidelines. Clinical validation analyses used the Medical Information Mart for Intensive Care IV (MIMIC-IV, v3.1) and the eICU Collaborative Research Database (eICU-CRD, v2.0), both hosted on PhysioNet. For the Medical Information Mart for Intensive Care IV (MIMIC-IV), the Institutional Review Board at the Beth Israel Deaconess Medical Center granted a waiver of informed consent and approved the sharing of the research resource. Use of the eICU Collaborative Research Database (eICU-CRD) is exempt from institutional review board approval owing to the retrospective design, lack of direct patient intervention, and the security schema, for which the re-identification risk was certified as meeting safe harbor standards by an independent privacy expert (Privacert, Cambridge, MA; Health Insurance Portability and Accountability Act Certification no. 1031219-2). Because all data are fully de-identified, individual informed consent was not required for this secondary analysis, which was conducted in accordance with the principles of the Declaration of Helsinki. Access was granted through PhysioNet credentialing, which includes completion of a recognized human subjects training course (CITI Program).","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"29943"}}