Protective effect of melatonin against age-related ischemia-reperfusion injury is associated with the NLRP3...

Aging heightens susceptibility to ischemia-reperfusion (IR) injury, complicating liver transplantation, while the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome drives IR- and aging-induced inflammation. Although the effects of melatonin (MLT) on IR or aging have been studied separately, its impact on NLRP3 inflammasome activation in age- related IR injury remains unclear. This study investigates the impact of aging on hepatic IR injury, evaluating MLT therapeutic potential. for mitigating age-related damage. Aged and young male Wistar rats underwent 60 min of ischemia followed by 6-24 h of reperfusion. MLT (1 mg/100 g body weight) was injected 30 min before ischemia, 10 min before reperfusion, and 2 h after reperfusion. Liver injury, oxidative stress and inflammatory responses, and activation of the NLRP3 inflammasome pathway were evaluated. Aged livers exhibited exacerbated IR injury, marked by elevated transaminases levels, severe histopathological damage, increased oxidative stress and heightened inflammatory responses compared to young IR-injured rats. MLT treatment significantly alleviated liver injury, reducing oxidative stress and inflammatory markers expression. Aging-associated IR injury correlated with increased NLRP3 inflammasome activation and pyroptosis, evidenced by the upregulation of apoptosis-associated speck-like protein containing a CARD (ASC-1), caspase-1 cleavage, interleukin (IL)-1β maturation and increased Il18 and Gsdmd gene expression; while MLT treatment suppressed this activation, downregulating these markers in aged IR-injured livers. These findings highlight the efficacy of MLT in mitigating IR-induced liver damage in aged rats by inhibiting the NLRP3 inflammasome activation, supporting its potential as a therapeutic strategy for age-related liver dysfunction.