Autophagy in Cadmium‐Induced Hepatic Injury of Rats: Protective Role of Naringenin

Cadmium, a bluish-white metallic, possesses a prolonged half-life in organisms, causing damage to multiple tissues and organs. Naringenin, a natural flavonoid antioxidant, mitigates cadmium-induced damage in organisms. However, the mechanism by which naringenin attenuates Cd-associated hepatocellular damage has not been fully elucidated. The present investigation consequently aimed to elucidate the mechanistic involvement of autophagy in cadmium hepatotoxicity using the rat model, with parallel assessment of naringenin's hepatoprotective efficacy. In this experiment, 24 SD rats underwent randomization to four experimental groups: (1) control (intraperitoneal saline injection), (2) Cd (1 mg/kg b.w. CdCl₂ intraperitoneal injection), (3) Cd + Nar (1 mg/kg b.w. CdCl₂ injection + 50 mg/kg b.w. naringenin oral gavage), and (4) Nar (50 mg/kg b.w. naringenin oral gavage) groups. After the 14-day interventions, serum and liver tissues were collected post-euthanasia. Hepatic injury markers (AST and ALT) and antioxidant enzymes (CAT and SOD) were quantified. Histopathology utilized HE and TUNEL staining. RT-qPCR and western blot analyses determined mRNA and protein expression levels of autophagy-related factors (p62 and LC3) and apoptosis-related factor (Caspase-3). The results demonstrated that cadmium exposure significantly reduced body weight, increased relative liver weight, elevated serum AST/ALT levels, and diminished hepatic CAT/SOD activity. Cadmium significantly upregulated both mRNA and protein expression levels of p62 and Caspase-3 while suppressing LC3 expression. Naringenin co-administration attenuated cadmium-induced hepatic injury, oxidative stress, impaired autophagy, and enhanced apoptosis. These findings collectively demonstrate that cadmium exposure induces hepatic injury and oxidative stress in rats through autophagy inhibition and apoptotic activation, while naringenin exerts protective effects by modulating these pathological processes.