Fig. 1

Molecular mechanisms related to the soluble molecules secreted (mediated by HBV) from hepatocytes and viral antigens that activate HSCs in a paracrine manner. In hepatocytes, HBX enhances TGF-β expression through Erg-1. In addition, HBsAg and preS2-Ag are involved in upregulation of TGF-β expression. HBX activates JNK and ERK to increase SATB1 expression levels, inhibits GSK-3β, sensitizes β-catenin, and activates the TGF-β/Smad2 pathway to upregulate CTGF expression. HBX increases HMGB1 expression levels, via activation of transcription factors GATA3, HSF1, ERBB3, TBP, KLF4, and NF-κB. The activation of STAT3 to restrict miR-34α and then activate NF-κB, the inhibition of GPR43, the activation of NLRP3, and the activation of CAMKK/CAMKIV pathway contributes to the increase of HMGB1 expression mediated by HBX. Depending on its interaction with TGF-βR, TGF-β activates the Smad2/3/4 pathway to enhance CD147 levels. CD147 activates HSCs by activating the ERK1/2 pathway and transcription factor Sp1. TGF-β upregulates miR-21-5p, miR-33a, and miR-942 to activate HSCs. miR-34α-5p can inhibit Smad4 to reduce HSC activation. Inhibition of miR-185 mediated by TGF-β promotes RICTOR and RHEB expression to sensitize HSCs. The OCT4/Nanog pathway also participates in TGF-β-mediated activation of HSCs. HMGB1 inhibits the mTOR and STAT3 pathways, but activates the JNK and ERK pathways, to induce autophagy and then activates HSCs. Additionally, the HBX mutation enhances Wnt5α expression to enhance HSC activation by activating the JNK and NFATc1 pathways. HBV promotes exosomes containing miR-222 and sensitizes HSCs by inducing TFRC-associated ferroptosis. Exosomes with HBX also activate HSCs