Jaafar Khaled: Endoplasmic reticulum stress signaling as a therapeutic target: Mechanisms and treatment response in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer and a leading cause of cancer-related mortality, often diagnosed at intermediate stages in patients with chronic liver disease. Transarterial chemoembolization (TACE) is the standard therapy for intermediate HCC, involving intra-arterial delivery of a chemotherapeutic agent emulsified in an oily carrier, followed by embolization of tumor-feeding vessels. HCC typically occurs in the context of prolonged inflammation and fibrosis, shaping a complex tumor microenvironment that promotes proliferation, epithelial-to-mesenchymal transition (EMT), and therapeutic resistance. Stromal components, such as hepatic stellate cells (HSCs), engage in tumor-stroma crosstalk that sustains fibrosis, angiogenesis, and inflammatory signaling, enhancing tumor development. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have emerged as central modulators of HCC progression and tumor stroma interactions. In the diseased liver, disruption of ER homeostasis activates the UPR via the PERK, IRE1α, and ATF6 pathways. Although the UPR is an adaptive response that aims to restore ER functions or induce apoptosis, its persistent activation may promote tumor cell survival, microenvironmental remodeling, and carcinogenesis.

In the present studies, complementary in vivo, in vitro, and ex vivo models were used to investigate the role of ER stress in HCC development, tumor-stroma crosstalk, and its potential as a therapeutic target. PERK inhibition with AMG-PERK reduced tumor burden, cell proliferation, fibrogenesis, and inflammation, while attenuating stromal activation via GP73 and GRP78-dependent signaling. Similarly, tauroursodeoxycholic acid (TUDCA) alleviated ER stress, reducing fibrogenesis, inflammation, and EMT, thereby limiting early hepatocarcinogenesis and underlining its preventive potential in chronic liver disease. Targeting IRE1α with the 4μ8C inhibitor reduced lipid metabolism, depriving tumor cells of energy reserves, and improving doxorubicin (DOX) cytotoxicity. In parallel, patient-derived 3D organoids (PDOs) were used to evaluate TACE-relevant chemotherapeutic responses. Organoid characterization revealed partial preservation of tumor architecture and phenotypic features. Treatment with idarubicin (IDA) reduced organoid growth dose-dependently with inter-patient variability in drug sensitivity, while showing greater potency than DOX. Therefore, this work provides mechanistic insights into HCC pathophysiology, highlights PDOs as a valuable experimental model and suggests that pharmacological modulation of UPR signaling could inhibit pro-tumorigenic pathways and improve treatment outcomes.