Cartilage Intermediate Layer Protein 2 Aggravates Hepatic Lipid Accumulation and Inflammation Through the IRE1α/XBP1 Pathway

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease and is characterized by excessive lipid accumulation in hepatocytes. Endoplasmic reticulum (ER) stress and inflammation play important roles in hepatic lipid accumulation. Although CILP2 has been implicated in lipid metabolism, its role in MASLD remains unclear. Hepatic steatosis was induced in mice by a high-fat diet in this study. CILP2 was overexpressed in mouse livers and in vitro hepatocytes using the Ad-CILP2 adenovirus. CILP2 KO mice were also used in the experiments. Liver tissues and hepatocytes were collected for further analysis. CILP2 expression was upregulated in steatotic liver tissue and hepatocytes. CILP2 overexpression upregulated genes related to fatty acid synthesis (<i>Srebp-1c, Fasn, Acc, Scd1, and Cd36</i>), promoted lipid accumulation, and elevated the expression of proinflammatory cytokines (<i>Il6, Tnf, and Il1b)</i>. Conversely, CILP2 knockout reduced high-fat diet-induced hepatic steatosis and improved glucose metabolism. Mechanistically, CILP2 activated the IRE1α/XBP1 branch of the ER stress pathway, thereby promoting lipid synthesis and inflammation, effects that were partially alleviated by 4-PBA and STF-083010 treatments. Our findings indicate that CILP2 contributes to hepatic lipid accumulation and inflammation via the IRE1α/XBP1 pathway and may represent a potential therapeutic target for MASLD intervention.