Table 1 Hypoxia-mediated HSCs activation is involved in the regulation of liver fibrosis by multiple mechanisms

Primary HSC

Cultured in 1% oxygen and 5% CO₂ balanced with N₂

Ca²⁺

Trigger Ca²⁺–AMPK–mTOR and PKCh activation, which leads to enhanced HSC autophagy

[12]

HSC-T6

Paeoniflorin

RTKs

HSCs inactivation through mTOR/HIF-1α signaling pathway

[9]

Cultured in 1% oxygen

HIF-1α

Hif-1α and MAPK co-regulate activation of HSC

[10]

Rosiglitazone

PPARγ

sGC/cGMP/PKG and PI3K/AKT signals act on PPARγ synergistically to attenuate hypoxia-induced HSC activation

[16]

LX-2

Stimulated by CoCl₂

TRPC6

1. Elevation of intracellular calcium which is coupled with the activation of the calcineurin-NFAT pathway which activates the synthesis of ECM

2. Activating SMAD2/3 dependent TGF-β signaling in facilitating upregulated expression of αSMA and collagen

[11]

Cultured in 0.3% O₂ and 5%CO_2, at 37 °C

HIF-1α

A positive feedback loop between HIF-1α and GAPDH, which promoting HSCs apoptosis under hypoxic conditions

[20]

Treated with EVs from hepatocytes which were treated with fatty acids and CoCl₂

EVs crosstalk

EVs from fat-laden hepatocytes undergoing chemical hypoxia evoke pro-fibrotic responses in LX-2 cells

[17]

Stimulated by CoCl₂

HIF-1α

Exosomes derived by HSCs was regulated by Hif-1. Exosomes containing glycolysis related proteins were involved in the activation and metabolic switch of HSCs and other liver nonparenchymal cells

[18]