Clec3b⁺ fibroblasts are the primary effectors of portal fibrosis following activation via a KLF4/periostin axis

Using single-cell RNA sequencing and genetic cell fate tracing in mouse models, we identified Clec3b⁺ fibroblasts as a distinct subset of portal fibroblasts, which rapidly expand after biliary injury and give rise to the bulk portal myofibroblasts. Mechanistic analyses revealed that Clec3b⁺ portal fibroblasts activation is governed by a Krüppel-like factor 4 (KLF4)/periostin (POSTN) axis, i.e., KLF4 directly binds the Postn promoter and represses its transcription in quiescent fibroblasts, whereas after injury, KLF4 is downregulated, which allows POSTN, acting via αvβ5 integrin, to drive portal fibroblast activation and portal fibrosis.

Our findings identify Clec3b+ portal fibroblasts as the primary effectors of portal fibrosis and demonstrate that the KLF4/POSTN signaling axis regulates their activation, offering potential therapeutic targets for inhibiting fibrosis in biliary diseases.