BackgroundNon-alcoholic steatohepatitis (NASH) is a major contributor to liver cirrhosis and hepatocellular carcinoma. There remains no effective pharmacological therapy. The hepatic lipid metabolism and fatty acid β-oxidation are regulated by Perilipin5 (Plin5). However, it is yet unknown how Plin5 affects NASH and the molecular process.MethodsHigh-fat, high-cholesterol and high-fructose (HFHC) diets were used to mimic the progression of NASH in wild type (WT) mice and Plin5 knockout (Plin5 KO) mice. The degree of ferroptosis was measured by detecting the expression of key genes of ferroptosis and the level of lipid peroxide. The degree of NASH was judged by observing the morphology of the liver, detecting the expression of inflammation and fibrosis related genes of liver damage. Plin5 was overexpressed in the liver of mice by tail vein injection of adenovirus, and the process of NASH was simulated by methionine choline deficiency (MCD) diet. The occurrence of ferroptosis and NASH was detected by the same detection method. Targeted lipidomics sequencing was used to detect the difference in free fatty acid expression in the WT Plin5 KO group. Finally, it was verified in cell experiments to further study the effect of free fatty acids on ferroptosis of hepatocytes.ResultsIn various NASH models, hepatic Plin5 was dramatically reduced. Plin5 knockout (KO) worsened NASH-associated characteristics in mice given a high-fat/high-cholesterol (HFHC) diet, such as lipid accumulation, inflammation and hepatic fibrosis. It has been shown that ferroptosis is involved in NASH progression. We revealed that Plin5 KO in mice aggravated the degree of ferroptosis in NASH models. Conversely, overexpression of Plin5 significantly alleviated ferroptosis and further ameliorated progression of MCD-induced NASH. Analysis of livers obtained from HFHC diet-fed mice by targeted lipidomics revealed that 11-Dodecenoic acid was significantly decreased in Plin5 KO mice. Addition of 11-Dodecenoia acid to Plin5 knockdown hepatocytes effectively prevented ferroptosis.ConclusionOur study demonstrates that Plin5 protects against NASH progression by increasing 11-Dodecenoic acid level and further inhibiting ferroptosis, suggesting that Plin5 has therapeutic potential as a target for the management of NASH.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12986-023-00751-2.