HBV infection upregulates GP73 expression to promote liver fibrosis by enhancing ER stress via the Smad2 pathway

Jun 26, 2025Immunologic research

HBV infection may increase GP73 levels to promote liver scarring by boosting cell stress through the Smad2 pathway

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Abstract

Knockdown of GP73 potentially impeded the advancement of liver fibrosis induced by hepatitis B virus (HBV) infection.

Elevated GP73 expression was observed following TGF-β1 stimulation in liver fibrosis cells.
Knockdown of GP73 reduced cell viability and proliferation in HBV-infected liver cells.
Markers of liver fibrosis and ER stress significantly increased with TGF-β1 treatment.
Silencing GP73 or applying 4-phenylbutyric acid counteracted the effects of TGF-β1 on liver fibrosis markers.
Opposite effects were noted after treatment with tunicamycin.

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Endoplasmic reticulum (ER) stress induced by hepatitis B virus (HBV) infection is associated with the development of liver fibrosis. Golgi protein 73 (GP73) is increased during HBV infection. Nevertheless, whether GP73 during HBV infection mediates ER stress in liver fibrosis is still poorly understood. TGF-β1 was used to induce HepG2.2.15 cells to establish liver fibrosis cells model. GP73 expression was evaluated using qRT-PCR analysis and Western blot. HepG2.2.15 cells viability and proliferation were assessed via CCK-8 assay and EdU assay, respectively. The protein levels of α-SMA, fibronectin, collagen I and collagen III for liver fibrosis, GRP78, p-PERK, p-eIF2α, ATF4 and CHOP for ER stress, as well as p-Smad2 and Smad2 were evaluated by Western blot. TGF-β1 incubation obviously elevated GP73 expression, while GP73 knockdown reduced the GP73 levels in HBV-transfected HepG2215 cells. GP73 knockdown reversed the effects of TGF-β1 exposure on HepG2.2.15 cells viability and proliferation. The protein levels of liver fibrosis marker, ERS marker and p-Smad2 were remarkably increased following TGF-β1 stimulation, which were counteracted by GP73 silence or the application of 4-phenylbutyric acid (4-PBA). However, these results were opposite after tunicamycin (TM) treatment. In conclusion, knockdown of GP73 potentially impeded the advancement of liver fibrosis via mediating ERs through Smad2 signal pathway.

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HBV infection upregulates GP73 expression to promote liver fibrosis by enhancing ER stress via the Smad2 pathway

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