Sex-Specific Downregulation of CDK5RAP3 Exacerbates ER Stress-Mediated Inflammation and Apoptosis in CCl4-Induced Acute Liver Injury

TL;DR

This study shows that lower CDK5RAP3 levels in males worsen liver damage through increased inflammation and cell death.

Contribution

The study identifies sex-specific roles of CDK5RAP3 in ER stress and liver injury mechanisms.

Findings

Male mice showed more severe liver injury and greater CDK5RAP3 downregulation after CCl4 treatment.

Reduced CDK5RAP3 increased ER stress, inflammation, and apoptosis in both mice and MEFs.

CDK5RAP3 deficiency worsened inflammatory and apoptotic responses in vitro.

Abstract

Background/Objectives: Sex-specific differences in the mechanisms of acute liver injury remain poorly understood. CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) is crucial for liver development and endoplasmic reticulum (ER) homeostasis. This study aimed to investigate sex-dependent changes in CDK5RAP3 expression in a carbon tetrachloride (CCl4)-induced acute liver injury model and to explore the mechanisms underlying differential susceptibility between males and females. Methods: Acute liver injury was induced in male and female mice by CCl4 administration. Liver injury was evaluated by serum biochemical parameters and histopathological analysis. CDK5RAP3 expression, inflammatory cytokines, and ER stress-related apoptotic markers were assessed. Hepatocyte apoptosis was examined by TUNEL staining. In addition, CDK5RAP3 was conditionally deleted in mouse embryonic fibroblasts (MEFs) using 4-hydroxytamoxifen to assess its direct role in regulating inflammatory and apoptotic responses in vitro. Results: CCl4 exposure caused liver injury in both sexes, with male mice showing more severe biochemical and histological damage. CDK5RAP3 expression was significantly reduced after CCl4 treatment, particularly in males. Inflammatory mediators and ER stress-associated apoptotic markers were upregulated, accompanied by increased hepatocyte apoptosis. A similar enhancement of inflammatory and apoptotic signaling was observed in CDK5RAP3-deficient MEFs. Conclusions: Downregulation of CDK5RAP3 is associated with ER stress, inflammation, and apoptosis, contributing to increased susceptibility of male mice to acute liver injury. These findings provide insight into sex-specific mechanisms of hepatic injury and highlight CDK5RAP3 as a potential therapeutic target.

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