Hepatic fibrosis is a chronic substantial liver injury caused by a variety of causes.1 It is mainly characterized by excess collagen and accumulation of extracellular matrix (ECM) and involves a variety of molecular and cellular biological processes.2 Activation of hepatic stellate cells (HSCs) is a critical component of hepatic fibrosis. After liver injury, HSCs change from static phenotype to activated phenotype with proliferation and contraction activity, and produce a large number of ECM components and inflammatory factor.3 TGF-β1 is an important cytokine driving fibrogenesis. It has been widely used to activate HSCs in vitro.4,5 Many studies have suggested that promoting apoptosis or inactivation of activated HSCs may be a novel strategy to promote fibrosis regression.6

TXNDC5 is a protein disulfide isomerase, most of which is located in the endoplasmic reticulum (ER) and Golgi apparatus. Through a series of disulfide bond exchange reactions, TXNDC5 helps the correct folding of newborn peptides and plays an important role in cell physiology.7 Studies have shown that abnormally high expression of TXNDC5 has been found in many types of human tumors, including liver cancer and lung cancer.8 More importantly, TXNDC5 can promote ECM protein folding and cardiac fibroblast activation, thereby enhancing myocardial fibrosis.9 Similarly, TXNDC5 plays a promoting role in the process of renal and pulmonary fibrosis.10,11 However, the role of TXNDC5 in hepatic fibrosis has not been reported.

Endoplasmic reticulum (ER) is the key place for protein folding and quality control. Rapid intracellular protein synthesis can lead to the imbalance of ER homeostasis, resulting in endoplasmic reticulum stress (ERs) and threatening cell function and survival.12 Severe or persistent ERs is associated with the progression of fibrotic disease.13 It has been reported that HMGB1 protein released from damaged hepatocytes can induce ERs by activating TLR4 and RAGE signaling pathways, thereby activating HSCs.14 Recent studies have shown that TXNDC5 can promote the proliferation and survival of colorectal cancer cells under hypoxia by inhibiting reactive oxygen species (ROS)/ERs signals.15 In addition, cetuximab can inhibit the expression of TXNDC5, thereby enhancing apoptosis associated with ERs.16 However, whether TXNDC5 is involved in hepatic fibrosis through the regulation of ERs is unclear.

The study aims to explore the role and mechanism of TXNDC5 in activated LX-2 cells and hepatic fibrosis mice. Our results showed that knockdown of TXNDC5 decreased the viability of activated HSCs and the expression of collagen COL1A1. Knockdown of TXNDC5 also promoted the apoptosis of activated HSCs by enhancing ERs. More importantly, knockdown of TXNDC5 alleviated CCl4-induced hepatic fibrosis in mice. These results suggest that targeting TXNDC5 may be a new approach to improving hepatic fibrosis.