Sema4D, also known as CD100, is a homodimeric protein belonging to the semaphorin family. It has immune functions, serving important roles in T cell priming, antibody production, and cell-to-cell adhesion. It exerts its effects through binding to receptors like PlexinB1, and is involved in multiple signaling pathways such as Src-dependent VE-cadherin dysfunction, PI3K/Akt, and RhoA/ROCK pathways, influencing various biological processes [3,4,6].

Genetic disruption of Sema4D/PlexinB1 or intravitreal injection of anti-Sema4D antibody alleviated vascular dysfunction in diabetic retinopathy models, reducing pericyte loss, vascular leakage, and neovascularization. Anti-Sema4D also showed a therapeutic advantage over anti-VEGF on pericyte dysfunction and had a synergistic effect with anti-VEGF [1]. In liver fibrosis models, knockout of Sema4D alleviated fibrosis by suppressing AOX1 expression in retinol metabolism and regulating the balance of Th1, Th2, Th17, and T-bet + Treg cells [2]. In a choroidal neovascularization model, Sema4D knockout attenuated CNV by inhibiting M2 macrophage polarization via regulation of the RhoA/ROCK pathway [6]. In osteosarcoma and AML models, knockdown or blocking of Sema4D inhibited cell proliferation, migration, invasion, and disease progression [4,5].

In conclusion, Sema4D plays crucial roles in various biological processes and diseases. Gene knockout models of Sema4D have revealed its functions in diabetic retinopathy, liver fibrosis, choroidal neovascularization, osteosarcoma, and AML, highlighting its potential as a therapeutic target in these disease areas.