Design, Synthesis, and Investigation of Anti-liver Fibrosis Activity of Steroidal VDR Modulators via Side-Chain Modifications.

Liver fibrosis, marked by excessive ECM deposition, can progress to cirrhosis and hepatocellular carcinoma, yet effective treatments are lacking. Since hepatic stellate cell (HSC) activation is central to fibrosis, inhibiting it is a key therapeutic strategy. Vitamin D receptor (VDR) activation can suppress HSC activation by inhibiting the TGFβ/SMAD3 pathway, making it a promising target. However, steroidal VDR agonists' clinical use is limited by hypercalcemia caused by upregulation of calcium metabolism genes. To overcome this, we designed novel steroidal VDR modulators by modifying the side chain to selectively impair transactivation of calcium-related genes while preserving antifibrotic signaling. Among 30 synthesized compounds, exhibited strong VDR affinity and potent antifibrotic activity in vitro. In a bile duct ligation mouse model, significantly alleviated liver fibrosis without inducing hypercalcemia, unlike calcipotriol. Mechanistically, inhibited the TGFβ/SMAD3 pathway without excessively upregulating calcium metabolism genes. Thus, represents a promising antifibrotic candidate warranting further investigation.