Naringenin cationic lipid-modified nanoparticles mitigate MASLD progression by modulating lipid homeostasis and gut microbiota.

Naringenin (NAR) possesses various pharmacological activities including antioxidant, anti-inflammatory, and hepatoprotective effects. However, its therapeutic efficacy is limited by its hydrophobic and crystalline nature. This study aimed to investigate the therapeutic potential and molecular mechanisms of NAR efficiently loaded into cationic nanoparticles (NP-NAR) for treating metabolic dysfunction-associated steatotic liver disease (MASLD) in a mouse model. The results demonstrated that NP-NAR effectively ameliorated lipid metabolism dysbiosis, oxidative stress, insulin resistance, and inflammation in MASLD mice. Transcriptomic analysis and molecular data revealed that NP-NAR promoted fatty acid oxidation via activation of the PPAR signaling pathway, reduced hepatic lipid uptake and lipogenesis by inhibiting the expressions of key genes including CD36, ACC, and FASN. Moreover, NP-NAR modulated cholesterol metabolism by inhibiting the classical bile acid synthesis pathway. 16 S rDNA gene sequencing revealed a disbalanced gut microbiota in MASLD mice, whereas NP-NAR treatment statistically reversed the abundance changes of several intestinal bacteria at the phylum and genus levels, which partly contributed to the balance in intestinal metabolite production, including short-chain fatty acids. In conclusion, these findings suggest that NP-NAR may be a promising candidate for the treatment of obesity-associated MASLD, offering new insight into the mechanisms underlying NAR's efficacy against MASLD.