Mechanistically, we demonstrated that miR-665-3p directly bound to the 3ʹ-untranslated region of fibronectin type III domain-containing 5 (FNDC5) to downregulate its expression and inactivated the downstream AMP-activated protein kinase alpha (AMPKα) pathway, thereby facilitating oxidative stress, inflammation and NAFLD progression. The gene discussed is FNDC5; the disease is metabolic dysfunction-associated steatotic liver disease.