Four mechanisms are involved in tissue remodeling; 1) Persistent inflammation by CHST15, 2) Activation of fibrosis pathway by CS-E, 3) Collagen fibril formation by CS-E and 4) Induction of mucosal damage by CS-E.
1) CHST15 (mRNA and protein) is induced during the activation of fibroblasts both from resident (or recruited) fibroblasts and epithelial cells [EMT].
- STNM01 inhibits the activation process, leading to reduced productions of IL-6, MCP-1/CCL2 and collagen by activated fibroblasts [myofibroblasts].
2) CS-E acts as a co-receptor for Wnt ligand and a direct receptor for RAGE, both leading to activation of fibrosis signaling pathways.
3) CS-E directly augments collagen fibril formation, leading to intractable fibrosis.
4) CS-E directly activates sulfate-reducing bacteria (SRB), leading to production of H2S and destruction of epithelial barrier. CS-E was also shown to have a cytostatic role through ROCK pathway. LAR family is the candidate receptor although still undefined in the gut system.
- STNM01 inhibits CS-E biosynthesis into ECM. STNM01 represses the excessive collagen deposition and promotes mucosal healing in clinical studies, indicating anti-tissue remodeling effect.
CHST15/CS-E is actively involved in tissue remodeling in fibrosis and cancer in multiple organs, indicating potential wider applications of CHST15 inhibitor.