Background/Objectives: Cadmium (Cd) is a harmful metal commonly used in industry. Numerous clinical diseases, including osteomalacia, testicular damage, renal and hepatic failure, and pulmonary edema, are associated with Cd exposure. The current study evaluated the protective effect of Sinapic acid (SA) against Cd-induced hepatotoxicity by investigating different mechanistic pathways interfering with Cd-related liver injury. Methods: Forty rats were randomly assigned to four groups as follows; group 1 served as negative control and received saline, group 2 received saline for 14 days and CdCl₂ (3.5 mg/kg IP) as a single dose on day 14, groups 3 and 4 were treated with SA (20, 40 mg/kg PO), respectively, for 14 days and injected with CdCl₂ (3.5 mg/kg IP) on day 14. Serum was collected to evaluate liver function. Liver samples were collected for histopathological examination and the assessment of markers related to oxidative stress, inflammation, and apoptosis. Results: Acute Cd administration elevated liver enzymes and induced pathological changes in liver specimens, with the concurrent release of inflammatory markers and reduced antioxidant capabilities. Pretreatment with SA improved liver function and Cd-induced histopathological changes and elevated the activities of antioxidant enzymes. SA ameliorated inflammation, as evidenced by decreased expression of NF-κB, TNF-α, TLR-4, and COX-2, iNOS, and IL-1β levels along with suppression of mTOR, JNK, ERK, BAX, and Bcl-2. Conclusions: The present data suggest that SA represents a promising protective agent against Cd-induced hepatic injury by attenuating oxidative stress, inflammation, and apoptosis.

Cadmium (Cd) is present in the environment in substantial quantities as a consequence of human activities, including the incineration of metal ores, the use of fossil fuels, and the burning of waste. Cd is a persistent heavy metal that does not degrade into less toxic forms and is excreted inefficiently from the body, leading to its bioaccumulation. Exposure to Cd can cause itai-itai disease and multiple organ dysfunction, including the lungs, testes, prostate, cardiovascular system, skeletal system, nervous system, and immune system. However, the primary sites of Cd accumulation are the liver, lungs, kidneys, and bones. At the cellular level, Cd induces toxicity through several mechanisms. One of the major pathways is the induction of oxidative stress, characterized by the excessive generation of reactive oxygen species (ROS) that overwhelm the cell’s antioxidant defense systems. This oxidative imbalance damages vital cellular components such as lipids, proteins, and DNA, leading to functional impairment and structural instability. In addition, Cd triggers inflammatory responses by activating pro-inflammatory signaling pathways and promoting cytokine production, contributing to chronic tissue inflammation and further exacerbating cellular injury. These disturbances disrupt cellular homeostasis and shift the balance toward cell death over survival, ultimately resulting in tissue and organ damage. This review aims to discuss the complex cellular events underlying Cd toxicity and their implications for human health.