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<p>Fibroblast-to-myofibroblast transition (FMT) and resistance to apoptosis are central drivers of fibrosis. Here, we report that sustained release of Calcium Sensing Receptor (CaSR) positive allosteric modulators (L-Phe, L-Trp, and cinacalcet) from electrospun p-dioxanone copolymer membranes exerts potent, ligand-specific anti-fibrotic effects. All formulations activated Gq-coupled CaSR, evoking ER-Ca<sup>2</sup>⁺ release and IP₃ generation. Differential recruitment of Gi yielded distinct cAMP/ROS signatures: cinacalcet (strong Gi bias) lowered cAMP and ROS levels, and suppressed AP-1, collagen-I and α-SMA expression; L-Trp (intermediate Gi) left cAMP unchanged while elevating ROS and inflammatory markers but nonetheless inhibited proliferation; L-Phe (weak Gi) raised cAMP, reduced ROS and fibrotic markers. Molecular docking confirmed Gi-coupling potency: cinacalcet (-125.4&#xa0;kJ&#xa0;mol⁻<sup>1</sup>) &gt; L-Trp (-101.7&#xa0;kJ&#xa0;mol⁻<sup>1</sup>) &gt; L-Phe (-75.5&#xa0;kJ&#xa0;mol⁻<sup>1</sup>). In a rat intestinal-adhesion model, cinacalcet and L-Phe membranes prevented adhesions and collagen deposition, whereas L-Trp only inhibited proliferation. Thus, these findings indicate that CaSR ligands tune fibroblast fate via Gi-biased receptor conformations and that ligand electrospun membranes constitute a versatile materials platform for precision antifibrotic therapy.</p> Graphical Abstract <p></p>

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Fibrosis suppressive effect and mechanism of CaSR positive allosteric modulators/p-dioxanone copolymers

  • 期刊论文

  • 发表日期：

    2026年4月14日

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  • Chengmin Feng,
  • Yuting Liu,
  • Chenghua Zhang,
  • Lijing Niu,
  • Jun Dong,
  • Bing Wang

摘要

Fibroblast-to-myofibroblast transition (FMT) and resistance to apoptosis are central drivers of fibrosis. Here, we report that sustained release of Calcium Sensing Receptor (CaSR) positive allosteric modulators (L-Phe, L-Trp, and cinacalcet) from electrospun p-dioxanone copolymer membranes exerts potent, ligand-specific anti-fibrotic effects. All formulations activated Gq-coupled CaSR, evoking ER-Ca2⁺ release and IP₃ generation. Differential recruitment of Gi yielded distinct cAMP/ROS signatures: cinacalcet (strong Gi bias) lowered cAMP and ROS levels, and suppressed AP-1, collagen-I and α-SMA expression; L-Trp (intermediate Gi) left cAMP unchanged while elevating ROS and inflammatory markers but nonetheless inhibited proliferation; L-Phe (weak Gi) raised cAMP, reduced ROS and fibrotic markers. Molecular docking confirmed Gi-coupling potency: cinacalcet (-125.4 kJ mol⁻1) > L-Trp (-101.7 kJ mol⁻1) > L-Phe (-75.5 kJ mol⁻1). In a rat intestinal-adhesion model, cinacalcet and L-Phe membranes prevented adhesions and collagen deposition, whereas L-Trp only inhibited proliferation. Thus, these findings indicate that CaSR ligands tune fibroblast fate via Gi-biased receptor conformations and that ligand electrospun membranes constitute a versatile materials platform for precision antifibrotic therapy.

Graphical Abstract