Anxa5, also known as Annexin V, is a calcium-dependent phospholipid-binding protein with a high affinity for phosphatidylserine (PS). This characteristic enables it to participate in multiple biological functions, such as vesicle transport, formation of mineral phases in the extracellular matrix, anticoagulation, antithrombotic processes, inhibition of tumor growth, and apoptosis regulation. It also has anti-inflammatory and antithrombotic properties, as well as protective effects on the nervous system [5].

In the context of recurrent pregnancy loss (RPL), the M2 haplotype of Anxa5 is associated with an increased risk of RPL. The M2 haplotype decreases the transcription efficiency of the Anxa5 promoter, leading to reduced Anxa5 expression in the placenta and peripheral blood of RPL patients [2,4]. A meta-analysis also shows that women with the M2/Anxa5 haplotype have a 1.54-fold higher odds of RPL compared with those with the normal haplotype, and male partners with the M2/Anxa5 haplotype also partly contribute to this risk [7]. In head and neck squamous cell carcinoma (HNSCC), Anxa5 is a gene with independent prognostic significance. Suppressing Anxa5 gene activity reduces the growth and mobility of HNSCC cells both in vitro and in vivo [1]. In stomach adenocarcinoma (STAD), increased Anxa5 expression is significantly correlated with poor overall survival and is an independent predictive factor of poor prognosis, and it is also significantly correlated with various infiltrating immune cells [3]. In hepatocellular carcinoma (HCC), Anxa5 is identified as a pivotal gene among anoikis-related genes, regulating immune cell infiltration, especially in mononuclear cells [6]. In non-alcoholic steatohepatitis (NASH), Anxa5 regulates hepatic macrophage polarization from M1 to M2 by directly targeting PKM2, improving steatosis, inflammation, and fibrosis in NASH mice [8].

In conclusion, Anxa5 is involved in a wide range of biological functions. Its study through genetic models has revealed its significance in diseases like RPL, HNSCC, STAD, HCC, and NASH. These findings provide valuable insights into the understanding of disease mechanisms and potential therapeutic targets related to Anxa5.

References:

1. Yang, Donghui, Chen, Huikuan, Zhou, Zheng, Guo, Jinfei. 2024. ANXA5 predicts prognosis and immune response and mediates proliferation and migration in head and neck squamous cell carcinoma. In Gene, 931, 148867. doi:10.1016/j.gene.2024.148867. https://pubmed.ncbi.nlm.nih.gov/39168258/

2. Zheng, Meiyun, Yan, Jinyu, Jiang, Lingling, Dai, Zhenzhen, Liu, Xiang. . Association between ANXA5 haplotypes and the risk of recurrent pregnancy loss. In The Journal of international medical research, 50, 3000605211026809. doi:10.1177/03000605211026809. https://pubmed.ncbi.nlm.nih.gov/35899914/

3. Su, Zhaoran, Shu, Kuanshan, Li, Guangyao. . Increased ANXA5 expression in stomach adenocarcinoma infers a poor prognosis and high level of immune infiltration. In Cancer biomarkers : section A of Disease markers, 35, 155-165. doi:10.3233/CBM-210482. https://pubmed.ncbi.nlm.nih.gov/35912732/

4. Cai, Zhuhua, Zheng, Xiuying, Chen, Yan, Chen, Liangmiao, Deng, Xiaohui. 2021. Genetic analysis of ANXA5 haplotype and its effect on recurrent pregnancy loss. In Molecular medicine reports, 25, . doi:10.3892/mmr.2021.12559. https://pubmed.ncbi.nlm.nih.gov/34878150/

5. Jin, Ming, Zhang, Jingrun, Sun, Yimeng, Liu, Ge, Wei, Xiaowei. 2025. ANXA5: related mechanisms of osteogenesis and additional biological functions. In Frontiers in cell and developmental biology, 13, 1553683. doi:10.3389/fcell.2025.1553683. https://pubmed.ncbi.nlm.nih.gov/40342928/

6. Wang, Weichen, Liu, Dongquan, Yao, Jiaming, Yan, Liang, Cao, Baoqiang. 2024. ANXA5: A Key Regulator of Immune Cell Infiltration in Hepatocellular Carcinoma. In Medical science monitor : international medical journal of experimental and clinical research, 30, e943523. doi:10.12659/MSM.943523. https://pubmed.ncbi.nlm.nih.gov/38824386/

7. Ang, Kai-Cheen, Bogdanova, Nadja, Markoff, Arseni, Ch'ng, Ewe Seng, Tang, Thean Hock. 2019. Association between M2/ANXA5 haplotype and repeated pregnancy loss: a meta-analysis. In Fertility and sterility, 111, 971-981.e2. doi:10.1016/j.fertnstert.2019.01.015. https://pubmed.ncbi.nlm.nih.gov/30922645/

8. Xu, Fang, Guo, Mengmeng, Huang, Wei, Wu, Xudong, Xu, Qiang. 2020. Annexin A5 regulates hepatic macrophage polarization via directly targeting PKM2 and ameliorates NASH. In Redox biology, 36, 101634. doi:10.1016/j.redox.2020.101634. https://pubmed.ncbi.nlm.nih.gov/32863213/