C3, a key complement protein, is at the core of all complement activation pathways. It's a crucial component of the innate immune system, enabling the detection and clearance of potential pathogens in association with other complement proteins [2]. C3 mediates multiple functions of the complement system via different binding sites and their corresponding receptors [1].

In myocardial ischemia/reperfusion (I/R) studies, C3 -/- mice showed decreased myocardial necrosis after heart I/R. Comparative proteomics analyses found cytochrome c in the myocardial C3 complex of wild-type mice following I/R. Exogenous human C3 reduced apoptosis in human cardiomyocytes and inhibited the intrinsic apoptosis pathway in a cell-free apoptosis system, indicating C3 reduces myocardial apoptosis via interaction with the intrinsic apoptotic pathway [3]. In gastric cancer, C3+ cancer-associated fibroblasts (CAFs) identified through animal studies and RNA sequencing promote tumor growth and therapeutic resistance. siRNA-mediated knockdown of C3 in CAFs in vitro showed that C3 secreted by CAFs promotes Epithelial-mesenchymal transition (EMT) and cancer cell migration. Enrichment analysis highlighted activation of the NF-κB signaling pathway in C3+ CAFs, suggesting targeting the NF-κB/C3 signaling axis in CAFs could be a therapeutic strategy for gastric cancer [4].

In conclusion, C3 is essential for the innate immune system and complement-mediated functions. Studies using gene knockout models, such as C3 -/- mice, have revealed its role in protecting against myocardial apoptosis during I/R and its contribution to gastric cancer progression. These findings enhance our understanding of biological processes and disease mechanisms related to C3, potentially guiding new therapeutic strategies.

References:

1. Zarantonello, Alessandra, Revel, Margot, Grunenwald, Anne, Roumenina, Lubka T. 2022. C3-dependent effector functions of complement. In Immunological reviews, 313, 120-138. doi:10.1111/imr.13147. https://pubmed.ncbi.nlm.nih.gov/36271889/

2. Delanghe, Joris R, Speeckaert, Reinhart, Speeckaert, Marijn M. . Complement C3 and its polymorphism: biological and clinical consequences. In Pathology, 46, 1-10. doi:10.1097/PAT.0000000000000042. https://pubmed.ncbi.nlm.nih.gov/24300728/

3. Fang, Zhou, Lee, Haekyung, Liu, Junying, Yang, Fajun, Zhang, Ming. 2023. Complement C3 Reduces Apoptosis via Interaction with the Intrinsic Apoptotic Pathway. In Cells, 12, . doi:10.3390/cells12182282. https://pubmed.ncbi.nlm.nih.gov/37759504/

4. Zhao, Zhenxiong, Xiong, Si, Gao, Jianpeng, Guo, Ergang, Huang, Yakai. 2024. C3+ cancer-associated fibroblasts promote tumor growth and therapeutic resistance in gastric cancer via activation of the NF-κB signaling pathway. In Journal of translational medicine, 22, 1130. doi:10.1186/s12967-024-05939-5. https://pubmed.ncbi.nlm.nih.gov/39707456/