Electroacupuncture Alleviates Oxidative Stress and Cuproptosis in Metabolic Dysfunction-Associated Steatotic Liver Disease Mice Through Activation of the NRF2/ARE Pathway

Purpose: Oxidative stress and the newly characterized mode of regulated cell death, cuproptosis, drive the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Electroacupuncture (EA) is a promising non-drug treatment, but its mechanisms are unclear. This study investigated the benefits of EA in a high-fat diet (HFD)-induced MASLD mouse model, focusing on the NRF2/ARE pathway, cuproptosis, and the gut-liver axis. Methods: MASLD was established in C57BL/6J mice via a 16-week HFD. Mice were arbitrarily categorized into four groups: control (C, normal chow diet), model (M, HFD), EA (HFD + EA), and EA plus NRF2 inhibitor (EM, HFD + EA + inhibitor). A 4-week intervention was then conducted. Post-intervention, body weight alterations were tracked, and serum, liver tissue, and fecal specimens were gathered for subsequent examination. Results: EA treatment significantly improved the metabolic profile, reducing body weight, lipids, and hepatic inflammation. It attenuated oxidative stress by enhancing antioxidant capacity and activated the NRF2/ARE pathway. EA also modulated cuproptosis-related genes (upregulating dihydrolipoamide S-acetyltransferase (Dlat), downregulating solute carrier family 31 member 1 (Slc31a1), ferredoxin reductase (Fdx1), and heat shock protein 70 (Hsp70)). Furthermore, EA remodeled the gut microbiota (increasing Limosilactobacillusand Ligilactobacillus) and elevated related metabolites. Conclusion: EA ameliorates MASLD through multiple mechanisms, including regulating lipid metabolism, attenuating inflammation and oxidative stress, activating NRF2, suppressing cuproptosis, and altering the gut-liver axis, collectively contributing to hepatic improvement.