Zfp469 Deletion Attenuates Liver Fibrosis by Suppressing Extracellular Matrix Production in Hepatic Stellate Cells.

Authors

Nantawat Satthawiwat, Archittapon Nokkeaw, Bootsakorn Boonkaew, Chinnatam Phetkong, Denita Charoenthanakitkul, Nuchanart Suntornnont, Ratchanon Wiphuosana, Thammachanok Boonto, Wirawit Srivongtrakul, Xinyu Wu, Chaiyaboot Ariyachet

Published in

Biomedical journal. Pages 101044. Sep 28, 2026. Epub Sep 28, 2026.

Abstract

Liver fibrosis is driven by excessive extracellular matrix (ECM) deposition following chronic injury. Mutations in the human zinc finger protein 469 (ZNF469) cause Brittle Cornea Syndrome, a systemic connective tissue disorder, yet its functional role in hepatic fibrogenesis remains unexplored in vivo. This study investigated the impact of the murine ortholog, Zfp469, on liver fibrosis using CRISPR-generated knockout (KO) models and integrated transcriptomic and cellular analyses.
Zfp469-KO and wild-type mice were subjected to chronic carbon tetrachloride (CCl₄) administration or a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Fibrosis was quantified via Masson's trichrome and Sirius Red staining. To assess cell-intrinsic effects, primary hepatic stellate cells (HSCs) were isolated for in vitro activation assays. Bulk and single-cell RNA sequencing datasets across toxic, metabolic, and cholestatic models were analyzed via pseudotime trajectory and single-cell co-expression network frameworks to map Zfp469 dynamics and network topology.
Zfp469 deficiency significantly attenuated collagen accumulation and mitigated the progression of liver injury in both toxin- and diet-induced models. Importantly, the loss of Zfp469 did not alter baseline liver morphology or homeostasis. At the cellular level, Zfp469-KO HSCs exhibited a blunted activation response with reduced expression of key myofibroblast markers (Col1a1, Col1a2, and Acta2) in vitro. Multi-model transcriptomic profiling demonstrated that Zfp469 is specifically enriched in activated HSCs, occupies key network modules, and exhibits etiology-dependent activation kinetics while maintaining a conserved pro-fibrotic gene signature.
This study provides the first in vivo evidence that Zfp469 is a critical, cell-autonomous regulator of hepatic ECM production. By demonstrating that Zfp469 is required for pathological fibrogenesis but dispensable for normal liver function, our findings identify the Zfp469-ECM axis as a promising therapeutic target for chronic liver diseases.

PMID:
42805497
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.