Tnfsf13, also known as A proliferation-inducing ligand (APRIL), is a cytokine of the tumor necrosis factor (TNF) superfamily. It plays a crucial role in B-cell maturation, survival, proliferation, and Ig class switching [2,5,6]. It is involved in multiple signaling pathways, and its dysregulation is associated with various diseases, highlighting its biological importance. Genetic models can be used to study its function in vivo.

In human colonic epithelial cells, TNFSF13 insufficiency disrupts B-cell differentiation. TNFSF13 variant colonoids showed reduced secreted TNFSF13, increased epithelial proliferation, and reduced apoptosis. This was also confirmed in iPSC-derived colon organoids. The study identified FAS as the predominant colonic epithelial receptor for TNFSF13, and found an increase in epithelial-associated B cells in TNFSF13 variant colon tissue. Co-culture of TNFSF13 variant colonoids with memory B cells led to a reduction in IgA+ plasma cell production [1].

In hypertrophic scar, TNFSF13 was up-regulated in HS skin tissues and HSF. Recombinant TNFSF13 protein increased HSF viability, proliferation, migration, fibrosis, and inflammation by activating the NF-κB signaling pathway through interaction with HSPG2. MSC-exo alleviated HS by inhibiting the fibroblasts via the TNFSF-13/HSPG2 signaling pathway [3].

In triple-negative breast cancer, TNFSF13 upregulation correlated with a poor response to chemotherapy as it promoted autophagy initiation in chemotherapeutic-resistant TNBCs. Targeting autophagy initiation could overcome TNFSF13-related chemoresistance, suggesting TNFSF13 could be a predictive biomarker for TNBC patients receiving chemotherapy [4].

In conclusion, Tnfsf13 is essential for B-cell-related functions and is involved in multiple disease processes. Studies using gene-related models, such as the TNFSF13-variant colonoids and in vitro cell models, have revealed its role in colonic epithelial-B-cell crosstalk, hypertrophic scar formation, and chemoresistance in triple-negative breast cancer. These findings contribute to understanding the biological functions of Tnfsf13 and its implications in related diseases.