Abstract

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, D13 exhibited strong VDR affinity and potent antifibrotic activity in vitro. In a bile duct ligation mouse model, D13 significantly alleviated liver fibrosis without inducing hypercalcemia, unlike calcipotriol. Mechanistically, D13 inhibited the TGFβ/SMAD3 pathway without excessively upregulating calcium metabolism genes. Thus, D13 represents a promising antifibrotic candidate warranting further investigation.