| Summary: | Alcohol intake at different developmental stages can lead to the development of alcohol-induced fatty liver disease (AFLD). Zingerone (ZO) possess hepato-protective properties; thus, when administered neonatally, it could render protection against AFLD. This study aimed to evaluate the potential long-term protective effect of ZO against the development of AFLD. One hundred and twenty-three 10-day-old Sprague–Dawley rat pups (60 males; 63 females) were randomly assigned to four groups and orally administered the following treatment regimens daily during the pre-weaning period from postnatal day (PND) 12–21: group 1—nutritive milk (NM), group 2—NM +1 g/kg ethanol (Eth), group 3—NM + 40 mg/kg ZO, group 4—NM + Eth +ZO. From PND 46–100, each group from the neonatal stage was divided into two; subgroup I had tap water and subgroup II had ethanol solution as drinking fluid, respectively, for eight weeks. Mean daily ethanol intake, which ranged from 10 to 14.5 g/kg body mass/day, resulted in significant CYP2E1 elevation (<i>p</i> < 0.05). Both late single hit and double hit with alcohol increased liver fat content, caused hepatic macrosteatosis, dysregulated mRNA expression of <i>SREBP1c</i> and <i>PPAR-α</i> in male and female rats (<i>p</i> < 0.05). However, neonatal orally administered ZO protected against liver lipid accretion and <i>SREBP1c</i> upregulation in male rats only and attenuated the alcohol-induced hepatic <i>PPAR-α</i> downregulation and macrosteatosis in both sexes. This data suggests that neonatal orally administered zingerone can be a potential prophylactic agent against the development of AFLD.
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