Canagliflozin Alleviates Metabolic Dysfunction-Associated Steatotic Liver Disease via Mitochondrial Protection and Enhanced Mitophagy.

Background: Canagliflozin shows anti-inflammatory and antioxidant properties. However, whether canagliflozin can mitigate metabolic dysfunction-associated steatotic liver disease (MASLD) by modulating mitochondrial dysfunction remains to be explored.

Methods: Canagliflozin was administered daily for MASLD mice at 10 mg/kg from Week 5 to Week 15. Biochemical assays were performed to assess serum triglyceride, total cholesterol, and liver damage markers. RT-qPCR was used to quantify the genes' expression involved in lipid synthesis and metabolism, whereas oil red O staining was utilized to visualize hepatic lipid accumulation. Western blot analysis was conducted to evaluate the expression of key proteins involved in mitochondrial damage and mitophagy.

Results: Canagliflozin treatment reduced liver hypertrophy, as shown by a lower liver weight/body weight ratio, and alleviated hepatic lipid accumulation with decreased triglyceride and total cholesterol levels. It improved the serum lipid profile by lowering low-density lipoprotein cholesterol and increasing high-density lipoprotein cholesterol through inhibiting lipid metabolism genes, including Srebf1, Fasn, and Cd36. Canagliflozin also reduced oxidative stress, as shown by lower malondialdehyde levels, and restored superoxide dismutase and catalase activity. Mitochondrial function was improved with increased ATP production and mitochondrial DNA content. Additionally, canagliflozin activated Parkin/PINK1-mediated mitophagy, as evidenced by upregulation of key mitophagy-related proteins such as PINK1, Parkin, and Atg7, as well as enhanced colocalization of LC3 and TOM20.

Conclusion: Our results demonstrate that canagliflozin may effectively treat MASLD by reducing liver fat and oxidative stress and improving mitochondrial function. It could be a promising treatment option for MASLD, particularly in diabetic patients.