S100 Calcium-Binding Protein 16 (S100A16) Promotes Hepatic Stellate Cell Activation Via Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2)-mediated Glycolysis to Facilitate Liver Fibrosis.

Authors

Shiyu Ou, Xiaoling Tang, Juan Liu, Rong Ouyang, Shijiang Huang, Shuwen Weng, Jinping Qin, Dingheng Liang, Ling Du, Zhongzhuan Li

Published in

Cell biochemistry and function. Volume 44. Issue 9. Pages e70299.

Abstract

Hepatic stellate cell (HSC) activation is a key mediator in hepatic fibrosis, with glycolysis serving a key regulatory function. S100 calcium-binding protein 16 (S100A16) has been associated with various pathologies; however, its function and underlying mechanisms in liver fibrosis remains elusive. This study aimed to elucidate the functional role of S100A16 in HSC activation and its interaction with Erb-B2 receptor tyrosine kinase 2 (ERBB2)-mediated glycolysis. Transforming growth factor-β1 (TGF-β1)-stimulated human liver stellate cells (LX2) and carbon tetrachloride (CCl₄)-induced mice were used as in vitro and in vivo models, respectively. Cell proliferation and alpha-smooth muscle actin (α-SMA) expression were detected by Cell Counting Kit-8 (CCK-8) assay and immunofluorescence. Glycolysis was detected via measuring the extracellular acidification rate (ECAR), lactate production, glucose uptake, and glycolytic enzyme levels. Molecular interactions were analyzed through bioinformatics and co-immunoprecipitation. Liver injury and fibrosis were assessed using hematoxylin and eosin (H&E)/Masson staining. Expression of S100A16, ERBB2, and fibrosis markers were quantified using quantitative real-time PCR (qRT-PCR) and Western blot. S100A16 was upregulated in fibrotic liver tissues and TGF-β1-stimulated LX2 cells. TGF-β1 increased lactate production and glycolysis, whereas S100A16 knockdown produced the opposite effects. Additionally, TGF-β1 enhanced cell proliferation and upregulated α-SMA, Collagen 1, and Fibronectin levels, but these effects were attenuated by either S100A16 knockdown or glycolysis inhibition. S100A16 interacted with ERBB2 and promoted its expression. ERBB2 knockdown reduced TGF-β1-induced glycolysis and HSC activation, along with reduced cell proliferation, effects that were inhibited by S100A16 overexpression. Furthermore, S100A16 knockdown ameliorated CCl₄-induced liver injury and fibrosis, decreased serum lactate levels, and reduced S100A16 and ERBB2 expression, thereby suppressing glycolysis. Collectively, S100A16 promotes HSC activation and liver fibrosis through ERBB2-mediated glycolysis, highlighting the S100A16-ERBB2-glycolysis axis as a potential therapeutic target.

PMID:
42704362
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

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