Sulforaphane preserves hepatocellular metabolic regulation and organelle integrity in a model of diet-induced obesity.

Metabolic-associated steatotic liver disease (MASLD) is strongly associated with obesity and type 2 diabetes (T2D), emerging as a consequence of sustained disturbances in hepatocellular metabolic signaling, inflammatory regulation, and organelle homeostasis induced by nutritional overload. Sulforaphane (SFN), a dietary bioactive compound, has been associated with metabolic protection, yet its ability to preserve hepatic cellular regulation and ultrastructural integrity during MASLD development remains incompletely defined. In this study, C57BL/6 mice were exposed to a high-fat, high-sucrose diet for 14 weeks to induce MASLD, with concomitant SFN administration (2 mg/kg/day, intraperitoneally, 5 days/week). Hepatic and adipose tissue remodeling, insulin signaling, inflammatory pathways, and subcellular architecture were evaluated using biochemical analyses, histology, gene expression profiling, and transmission electron microscopy. SFN markedly attenuated hepatic steatosis, collagen deposition, and glycogen degeneration, while modulating insulin signaling pathway and shifting hepatic gene expression toward oxidative metabolic pathways. These effects were accompanied by suppression of inflammatory mediators, including Nlrp3, Tnfa, and Il1β. At the ultrastructural level, SFN preserved mitochondrial architecture and endoplasmic reticulum organization, preventing diet-induced organelle stress, lipid overload and energy imbalance. Collectively, these findings demonstrate that SFN protects against diet-induced MASLD by maintaining hepatocellular metabolic and inflammatory regulation and preserving organelle integrity, highlighting the relevance of cellular regulatory mechanisms in the control of hepatic intermediary metabolism.