Biomedical journal · 2026
Zfp469 Deletion Attenuates Liver Fibrosis by Suppressing Extracellular Matrix Production in Hepatic Stellate Cells.
СтатьяНазвание и аннотация: Перевод в очереди
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Satthawiwat Nantawat, Nokkeaw Archittapon, Boonkaew Bootsakorn, Phetkong Chinnatam, Charoenthanakitkul Denita, Suntornnont Nuchanart, Wiphuosana Ratchanon, Boonto Thammachanok, Srivongtrakul Wirawit, Wu Xinyu, Ariyachet Chaiyaboot
Аннотация
BACKGROUND: 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.
MATERIALS AND METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
MATERIALS AND METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.