ER Stress as the Molecular Bridge Between MASH and Hepatocellular Carcinoma- Hepatology Feb.26

Metabolic dysfunction–associated steatohepatitis (MASH) is rapidly becoming a leading driver of hepatocellular carcinoma (HCC). This comprehensive review highlights endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) as a central molecular link connecting chronic metabolic liver injury to malignant transformation.

Hepatocytes are highly dependent on ER function to manage lipid metabolism, protein synthesis, and detoxification. In MASH, excess lipids, oxidative stress, and inflammation overwhelm ER proteostasis, leading to persistent activation of the UPR. While short-term UPR signaling is adaptive, chronic ER stress promotes inflammation, fibrosis, genomic instability, and altered cell death pathways, all of which favor progression toward cirrhosis and HCC.

The review details how the three major UPR branches—IRE1/XBP1, PERK/ATF4, and ATF6—exert context-dependent effects across hepatocytes, hepatic stellate cells, endothelial cells, and immune cells. Sustained activation of these pathways reshapes the tumor microenvironment, enhances fibrogenesis, suppresses antitumor immunity, and contributes to resistance to systemic therapies such as sorafenib. ER stress signaling also influences immune evasion through macrophage polarization, dendritic cell dysfunction, and PD-L1 regulation.

Importantly, ER stress pathways represent actionable therapeutic targets. Preclinical studies suggest that selectively modulating UPR signaling—either by inhibiting adaptive survival pathways or pushing cells toward terminal stress—may sensitize tumors to chemotherapy and immunotherapy while also limiting fibrosis.

In summary, chronic ER stress is a unifying driver of MASH progression and hepatocarcinogenesis. Targeting UPR signaling offers a promising avenue for combination therapies aimed at preventing or treating HCC in patients with metabolic liver disease.