PPL

Periplakin (PPL) marks a morphologically distinct, pro-regenerative subset of cholangiocytes that restrains liver fibrosis and promotes hepatic regeneration (PMID:42141833). PPL overexpression reduces DDC-induced fibrosis whereas its knockdown aggravates it, and adoptive transfer of FACS-sorted PPL+ cholangiocytes improves liver function, lowers collagen deposition, raises matrix metalloproteinases (MMP2/12/13/14) and anti-inflammatory and growth factors (IL-10, EGF, HGF) while reducing TGF-β1 and TIMP1, and enhances hepatocyte proliferation (PMID:42141833). PPL+ cholangiocytes drive hepatocyte activation through a paracrine NRG1-ERBB3-PI3K/AKT signalling axis (PMID:42141833). Beyond this cholangiocyte regenerative role, no further molecular characterization of PPL has been established in the available corpus.

1. 2026 Medium

   It was unknown whether a specific cholangiocyte subpopulation could attenuate liver fibrosis; this work established PPL as a marker of a pro-regenerative cholangiocyte subset whose abundance bidirectionally controls fibrotic outcome and hepatocyte proliferation.

   Evidence Single-nucleus RNA-seq with adenoviral/AAV overexpression and knockdown, FACS sorting and adoptive transfer, hepatocyte co-culture, and CellChat signalling inference in a DDC liver fibrosis model

   PMID:42141833

   Open questions at the time

   • NRG1-ERBB3-PI3K/AKT axis validated in vitro but not independently replicated
   • The intrinsic molecular/cytoskeletal function of PPL within cholangiocytes was not defined
   • Whether PPL is causally required for the regenerative phenotype versus a correlated marker is not fully resolved

• The biochemical activity of PPL, its direct molecular partners, and the mechanism by which it specifies the pro-regenerative cholangiocyte state remain undefined.
• No defined molecular activity or interaction partner for the PPL protein itself
• No structural or subcellular mechanistic characterization in this context