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, 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.