3044-LB: Body Weight–Independent Reduction in Hepatic Steatosis and Inflammation by Ethanolic Extract of Cucumis melo var. makuwa Leaves in HFD-Induced MASLD

Introduction and Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis and inflammatory stress, yet adjunctive strategies that improve hepatic outcomes independent of body weight reduction remain limited. We investigated whether 70% ethanolic extract of Cucumis melo var. makuwa leaves (CML) reduces hepatic steatosis and inflammation in HFD-induced MASLD independent of body weight change. Methods: Male C57BL/6J mice were fed a normal diet or HFD with or without CML (0.4% or 0.8%) for 18 weeks. Body weight, food intake, OGTT/ITT, liver weight, serum ALT, hepatic triglyceride and total cholesterol, hepatic ROS/ONOO-, and histologic steatosis were assessed. Primary hepatocytes were treated with CML and free fatty acids (FFA) to evaluate direct effects on lipid accumulation, and RNA-seq was performed to identify CML-responsive pathways. Results: CML did not significantly affect body weight, food intake, or energy expenditure, indicating a body weight-independent effect. CML improved glucose tolerance, whereas its effect on insulin tolerance was limited. In HFD-fed mice, 0.8% CML reduced hepatic steatosis, liver weight, serum ALT, hepatic triglyceride and total cholesterol (both p < 0.001), and hepatic ROS/ONOO- generation (p < 0.001). In primary hepatocytes, CML reduced FFA-induced lipid accumulation, with the strongest effect at 200 ppm (p < 0.001). RNA-seq in FFA-exposed primary hepatocytes showed suppression of inflammatory pathways, including IL-17 signaling, leukocyte migration, and cytokine-mediated signaling. Conclusion: CML reduced hepatic steatosis and inflammatory stress in HFD-induced MASLD independent of body weight change, supporting its potential as an adjunctive strategy for improving hepatic outcomes in MASLD. Disclosure Y. Seong: None. J. Van: None. J. Kim: None. B. Lee: None. Funding This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2021-NR060118). This research was also supported by the National Research Foundation of Korea (RS-2023-00274576). This research was a part of the project titled 'Global bluefood leadership project (RS-2025-02373103)', funded by the Ministry of Oceans and Fisheries, Korea.