Update on XBP1 in liver pathobiology

Chronic liver disease is a major cause of global morbidity and mortality, yet disease-modifying therapies remain scarce. A shared mechanism uniting metabolic, alcohol-associated, viral, drug-induced, cholestatic, and genetic liver injury is endoplasmic reticulum stress and activation of the unfolded protein response. The transcription factor X-box binding protein 1-spliced, a principal output of the inositol-requiring enzyme 1α arm of this response, has emerged as a central determinant of disease pathogenesis. Under endoplasmic reticulum stress, inositol-requiring enzyme 1α splices X-box binding protein 1 messenger RNA to generate the spliced protein, which increases protein folding and degradation capacity and governs hepatic lipogenesis and lipoprotein assembly. A defining feature, however, is its functional dichotomy: typically cytoprotective in hepatocytes but pathogenic in macrophages and stellate cells, and adaptive during transient but maladaptive during unresolved or excessive stress. This dichotomy sans the spectrum of liver diseases and explains, in part, why global manipulation of the pathway has yielded conflicting results and has obstructed targeted drug development. In conclusion, cell-type selectivity is the central translational challenge, preserving protective hepatocyte signaling while restraining it in non-parenchymal cells, which may be addressed through targeted delivery of pharmacologic or genetic therapeutics directed at this pathway in animal models and humans.