C-reactive protein (CRP) is a plasma protein that is evolutionarily conserved and plays a crucial role in innate immune responses. It is a member of the pentraxin superfamily, characterized by its pentameric structure and calcium-dependent binding to ligands like phosphocholine (PC). CRP exhibits contrasting biological functions due to conformational transitions, while retaining conserved protective functions in various species. This review focuses on the structural traits of CRP, its regulation, and its role in clinical diseases. CRP is primarily synthesized in the liver and is a prototypical acute phase protein that increases significantly during inflammatory conditions. It can bind to various pathogens and has calcium-dependent binding properties to chromatin, histones, and glycans. The molecular weight of human CRP is approximately 115 kDa, and it consists of five identical subunits that form a cyclic pentamer. The pentamer has a "jelly-like lectin fold" and contains a calcium-binding pocket and a single α-helix for ligand binding. CRP's expression is regulated by transcription factors such as STAT3, Rel p50, c-Rel, and C/EBPβ/δ. Post-transcriptional regulation also plays a role, with carboxylesterase reducing the binding capability of CRP in the endoplasmic reticulum, leading to its secretion during the acute phase. The promoter methylation status of the CRP gene is influenced by DNMT3A and TET2, affecting gene expression. CRP has been studied in both human and experimental animal models, particularly in mice and rats. While CRP behaves differently in these species, it has been shown to have a protective effect on acute liver injury and delay death caused by sepsis. CRP is also associated with various diseases, including cardiovascular disease, systemic lupus erythematosus (SLE), cancer, and viral infections. Elevated CRP levels are often correlated with disease severity and can serve as biomarkers for monitoring disease progression and treatment responses. In conclusion, CRP plays a critical role in innate immunity and inflammation, and its understanding is essential for developing therapeutic strategies. However, the functional differences between human and animal models require further research to optimize experimental designs and confirm the role of CRP in diseases.C-reactive protein (CRP) is a plasma protein that is evolutionarily conserved and plays a crucial role in innate immune responses. It is a member of the pentraxin superfamily, characterized by its pentameric structure and calcium-dependent binding to ligands like phosphocholine (PC). CRP exhibits contrasting biological functions due to conformational transitions, while retaining conserved protective functions in various species. This review focuses on the structural traits of CRP, its regulation, and its role in clinical diseases. CRP is primarily synthesized in the liver and is a prototypical acute phase protein that increases significantly during inflammatory conditions. It can bind to various pathogens and has calcium-dependent binding properties to chromatin, histones, and glycans. The molecular weight of human CRP is approximately 115 kDa, and it consists of five identical subunits that form a cyclic pentamer. The pentamer has a "jelly-like lectin fold" and contains a calcium-binding pocket and a single α-helix for ligand binding. CRP's expression is regulated by transcription factors such as STAT3, Rel p50, c-Rel, and C/EBPβ/δ. Post-transcriptional regulation also plays a role, with carboxylesterase reducing the binding capability of CRP in the endoplasmic reticulum, leading to its secretion during the acute phase. The promoter methylation status of the CRP gene is influenced by DNMT3A and TET2, affecting gene expression. CRP has been studied in both human and experimental animal models, particularly in mice and rats. While CRP behaves differently in these species, it has been shown to have a protective effect on acute liver injury and delay death caused by sepsis. CRP is also associated with various diseases, including cardiovascular disease, systemic lupus erythematosus (SLE), cancer, and viral infections. Elevated CRP levels are often correlated with disease severity and can serve as biomarkers for monitoring disease progression and treatment responses. In conclusion, CRP plays a critical role in innate immunity and inflammation, and its understanding is essential for developing therapeutic strategies. However, the functional differences between human and animal models require further research to optimize experimental designs and confirm the role of CRP in diseases.