{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T16:41:36Z","timestamp":1786725696553,"version":"build-2736575974"},"reference-count":56,"publisher":"Bioscientifica","issue":"2","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), remains a major health concern worldwide. Hepatic steatosis manifests by the aberrant accumulation of lipids in hepatocytes. We have previously shown that pharmacological inhibition of mTOR complex 1 (mTORC1) by rapamycin, a widely utilized potent immunosuppressant, induces MASLD under normal conditions. Notably, this phenotype was found exacerbated in mice with genetic or pharmacological inhibition of the master transcriptional regulator of energy metabolism, nuclear receptor ERR\u03b1. In this study, we show that combining antimalarial drug chloroquine with rapamycin attenuates the severity of hepatic lipid deposition observed with rapamycin monotherapy. Bulk mRNA-seq profiling showed that chloroquine co-injection reverses the upregulation of a large proportion of genes linked to lipid metabolism homeostasis found induced by rapamycin alone. Interrogation of these genes for direct transcriptional regulators identified ERR\u03b1 among top candidates. Using a mouse model with genetic ERR\u03b1 ablation, we demonstrate a crucial dependency on ERR\u03b1 activity for the observed amelioration of rapamycin-induced hepatic steatosis by chloroquine addition. In ERR\u03b1-null liver, chloroquine failed to reverse and, in some instances, aggravated the upregulation of lipid metabolism genes by rapamycin, with evidence linking the impaired management of hepatic lipid overload to the underlying mitochondrial dysfunction. Together, these findings underscore a critical role of ERR\u03b1 in reversing MASLD.<\/jats:p>","DOI":"10.1530\/joe-26-0176","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T10:57:13Z","timestamp":1785754633000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":0,"title":["Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERR\u03b1-dependent manner"],"prefix":"10.1530","volume":"270","author":[{"given":"Wafa","family":"B\u2019chir","sequence":"first","affiliation":[{"name":"Goodman Cancer Institute, McGill University 1 , , ,","place":["Montr\u00e9al, Qu\u00e9bec, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine R","family":"Dufour","sequence":"additional","affiliation":[{"name":"Goodman Cancer Institute, McGill University 1 , , ,","place":["Montr\u00e9al, Qu\u00e9bec, 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,","place":["Montr\u00e9al, Qu\u00e9bec, Canada"]},{"name":"Universit\u00e9 Lyon 1, INSERM, INRAE, CarMeN 4 , ,","place":["Pierre-B\u00e9nite, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9567-3694","authenticated-orcid":true,"given":"Vincent","family":"Gigu\u00e8re","sequence":"additional","affiliation":[{"name":"Goodman Cancer Institute, McGill University 1 , , ,","place":["Montr\u00e9al, Qu\u00e9bec, Canada"]},{"name":"Department of Biochemistry, School of Biomedical Sciences, Faculty of Medicine and Health Sciences, McGill University 5 , , ,","place":["Montr\u00e9al, Qu\u00e9bec, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"2026081412020957000_bib1","doi-asserted-by":"crossref","DOI":"10.1016\/j.aohep.2023.101133","article-title":"2024 A multisociety Delphi consensus statement on new fatty liver disease 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