What question did this study set out to answer?

To investigate if SIRT3 protects bovine hepatocytes from ferroptosis caused by elevated NEFA levels.

February 28, 2026Journal of Agricultural and Food Chemistry0 citations

Nonesterified Fatty Acids Cause Hepatic Ferroptosis in Dairy Cows via SIRT3-JNK Signaling

Key Points

To investigate if SIRT3 protects bovine hepatocytes from ferroptosis caused by elevated NEFA levels.
Cultured bovine hepatocytes exposed to high NEFA for ferroptosis assessment.
Lipid peroxidation measurements and ultrastructure observations to confirm ferroptosis.
RNA sequencing to investigate gene expression changes associated with SIRT3 overexpression.
JNK signaling pathway analysis using agonist assays.
High NEFA levels caused significant ferroptosis in bovine hepatocytes.
SIRT3 overexpression reduced NEFA-induced ferroptosis manifestations.
Increased JNK signaling activity was observed in dairy cows with fatty liver.
Hepatic SIRT3 protein levels were lower in cows with fatty liver.

Abstract

Elevated nonesterified fatty acid (NEFA) levels, resulting from excessive fat mobilization, are recognized as the pathological basis for fatty liver in dairy cows. Hepatotoxicity of high NEFA is antagonized by the activity of Sirtuin 3 (SIRT3). However, it is unclear whether SIRT3 antagonizes ferroptosis in bovine hepatocytes. Hence, we aimed to investigate the interplay between NEFA and SIRT3 on ferroptosis. High NEFA caused ferroptosis in cultured bovine hepatocytes, as validated by lipid peroxidation measurement, ultrastructure observation, and key gene expression. SIRT3 overexpression alleviated high NEFA-induced ferroptosis. RNA-seq revealed that NEFA-induced ferroptosis was inhibited by SIRT3 through the JNK signaling pathway, and this was further confirmed by the JNK signaling agonist assay. Dairy cows with fatty liver showed reduced hepatic SIRT3 protein levels alongside heightened JNK signaling activity. These results highlight the potential for targeting the SIRT3-JNK axis to prevent or alleviate NEFA-induced hepatotoxicity during the periparturient period.

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