The Journal of endocrinologyAug 3, 2026

Chloroquine reduces rapamycin-caused fatty liver in mice through a pathway involving ERRα

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 4, 2026

Abstract

Combining chloroquine with rapamycin reduces hepatic lipid deposition in a mouse model of metabolic dysfunction-associated steatotic liver disease (MASLD).

Pharmacological inhibition of mTOR complex 1 by rapamycin is associated with the development of MASLD.
Chloroquine co-injection attenuates the severity of hepatic lipid accumulation induced by rapamycin.
Gene profiling reveals that chloroquine reverses the upregulation of many genes related to lipid metabolism that are activated by rapamycin.
ERRα is identified as a key transcriptional regulator linked to the effects of chloroquine on lipid metabolism.
In mice lacking ERRα, chloroquine does not reverse the lipid metabolism gene changes caused by rapamycin and may worsen them.
Impaired management of hepatic lipid overload in ERRα-deficient mice is associated with mitochondrial dysfunction.

Simplified

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), remains a major health concern world-wide. 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 ERRα. In this study, we show that combining antimalaria 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 ERRα among top candidates. Using a mouse model with genetic ERRα ablation, we demonstrate a crucial dependency on ERRα activity for the observed amelioration of rapamycin-induced hepatic steatosis by chloroquine addition. In ERRα-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 underling mitochondrial dysfunction. Together, these findings underscore a critical role of ERRα in reversing MASLD.

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Chloroquine reduces rapamycin-caused fatty liver in mice through a pathway involving ERRα

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