Shikonin Ameliorates Alcohol‐Associated Liver Disease by Reducing Oxidative Stress, Apoptosis, and Inflammation

Alcohol-associated liver disease (ALD) represents a major global health concern due to its significant contribution to morbidity and mortality. The development of ALD is largely driven by oxidative stress, inflammation, and apoptosis. Shikonin (SKN) is a natural extract possessing both antioxidant and anti-inflammatory properties. This study investigated the protective effects of SKN against ALD in an in vivo rat model of ALD induced by daily gavage with 52% alcohol for 6 weeks. Following this, SKN was administered, and its antioxidant, anti-inflammatory, and anti-apoptotic properties were examined. Results demonstrated that SKN treatment inhibited the alcohol-induced increase of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total cholesterol (TC), triglycerides (TG), lipopolysaccharide (LPS), reactive oxygen species (ROS), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in serum and liver tissue, while enhancing the anti-inflammatory factor IL-10. Moreover, SKN mitigated alcohol-induced histological changes in liver tissues. In addition, the administration of SKN led to the restoration of hepatic superoxide dismutase (SOD) levels while reducing malondialdehyde (MDA) levels. Western blot revealed that SKN notably decreased Keap1 expression and elevated the expression of Nrf2 and HO-1 proteins, thereby enhancing the antioxidant capacity. In addition, SKN mitigated inflammation by inhibiting the TLR4/MyD88/NF-κB pathway. Furthermore, SKN administration inhibited the expression of Bax and Caspase3, while upregulating the anti-apoptotic protein Bcl-2, thereby reducing hepatocyte injury through the inhibition of apoptosis. Overall, these results indicated that SKN could ameliorate ALD by mitigating oxidative stress, apoptosis, and inflammation, positioning it as a promising natural extract for preventing and treating ALD.