Polystyrene nanoplastics (PS-NPs) are ubiquitous environmental pollutants that can cause oxidative stress in various organs, including the liver. Didymin is a dietary flavanone that displays multiple pharmacological activities. Therefore, the present study evaluated the palliative role of didymin against PS-NPs-induced hepatic damage in rats. Albino rats (n=48) were randomly distributed into 4 groups: control, PS-NPs treated group, PS-NPs + didymin co-administered group, and didymin supplemented group. After 30 days, PS-NPs intoxication lowered the expression of
Nrf-2
and anti-oxidant genes [catalase
(CAT),
superoxide dismutase
(SOD),
glutathione peroxidase
(GPx),
glutathione reductase
(GSR),
glutathione-S-transferase
(GST),
and heme oxygenase-1
(HO-1
)], whereas the expression of KEAP1 kelch like ECH associated protein 1 (Keap-1) was increased. PS-NPs exposure also reduced the activities of anti-oxidants enzymes (CAT, SOD, GPx, GSR, GST, GSH, and OH-1), while malondialdehyde (MDA) and reactive oxygen species (ROS) levels were increased. The levels of alanine transaminase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were increased in PS-NPs-exposed rats. Moreover, inflammatory indices [interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), nuclear factor-kappa B (NF-κB), and cyclooxygenase-2 (COX-2)] were increased in PS-NPs-exposed rats. Furthermore, PS-NPs intoxication increased the expressions of apoptotic markers including
Bax
and
Caspase-3
, as well as reducing
Bcl-2
expression. The histopathological analysis showed significant damage in PS-NPs-treated rats. However, didymin supplementation ameliorated all the PS-NPs-induced damage in the liver of rats. Therefore, it was concluded that didymin can act as a remedy against PS-NPs-induced liver toxicity due to its anti-apoptotic, anti-oxidant, and anti-inflammatory activities.