ER stress in hepatocytes induces PHLDA3 via IRE1-Xbp1s pathway, which facilitates liver injury by inhibiting Akt.

A new microbial secondary metabolite, paulobutalipin (<b>1</b>), was isolated and characterized from the culture of a mountain soil-derived <i>Streptomyces</i> strain. The structure of paulobutalipin (<b>1</b>) was elucidated through a combined analysis of spectroscopic data, single-crystal X-ray diffraction, chemical modifications including application of the modified Mosher's method, and electronic circular dichroism calculations. In an in vitro hepatocellular steatosis model induced by palmitic and oleic acids, paulobutalipin (<b>1</b>) reduced intracellular lipid accumulation in AML12 hepatocytes by approximately 30% compared to that of vehicle controls. Moreover, it enhanced mitochondrial abundance in a dose-dependent manner, suggesting stimulation of mitochondrial β-oxidation. Our data identify paulobutalipin as a unique microbial natural product that promotes energy metabolism possessing structural complexity and minimal toxicity.

Elevated liver stiffness is closely associated with morbidity and mortality in metabolic dysfunction-associated steatotic liver disease (MASLD). However, the contribution of increased stiffness to impaired liver function is poorly understood. Here, we demonstrate that hepatic cholesterol levels are determined by the stiffness of the liver. In the human MASLD cohort and a mouse model, intrahepatic cholesterol levels strongly correlated with liver stiffness. We show that a stiff matrix promotes spontaneous accumulation of cholesterol in isolated hepatocytes. As the underlying mechanism, we found that Liver X receptor alpha (LXRα) is mechanosensitively repressed. Activation of Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ) by exposure to stiff substrate, serum stimulation, low-density culture, or deletion of Large tumor suppressor kinase 1 and 2 (LATS1/2) robustly repressed LXRα activity. In the nucleus, YAP disrupted heterodimerization of LXRα with Retinoid X receptor alpha (RXRα) independently of their transcriptional activity. Consistently, hepatocyte-specific ablation of Yap/Taz facilitated hepatic cholesterol efflux and delayed cholesterol-induced fibrosis progression in mice. Transcriptomic analysis of MASLD patient livers confirmed a strong inverse correlation between LXRα target gene expression and liver stiffness as well as YAP/TAZ activity. These findings reveal the mechanosensitive regulation of hepatic cholesterol levels in MASLD, suggesting liver stiffness as a causal factor for hepatocyte dysfunction.

Hepatic ischemia-reperfusion injury (HIRI) is a major complications associated with liver transplantation, contributing to graft rejection and liver dysfunction. Early detection of ischemic damage prior to reperfusion is crucial for improving clinical outcomes. While previous studies have primarily focused on detecting reactive oxygen species (ROS) generated during IRI, specific detection of ischemic injury itself, characterized by hypoxia, remains underexplored. Here, we developed <b>QN-NIR</b>, a near-infrared (NIR) fluorescent probe designed for dual activation by two hypoxia-associated reductases, human NAD(P)H:quinone oxidoreductase 1 (hNQO1) and nitroreductases (NTRs). Both enzymes are upregulated under hypoxic conditions, and their activation of <b>QN-NIR</b> triggers a strong Off-On NIR fluorescence response at 708 nm. This dual-enzyme strategy offers high signal-to-noise (s/n) contrast with minimal false-positive signals under normoxic conditions. <b>QN-NIR</b> enables precise, real-time visualization of hepatic ischemia prior to reperfusion in vivo, thereby supporting the potential of hypoxia as a key and directly targetable feature of ischemic injury. While further studies are needed to fully delineate its clinical applicability, this work highlights <b>QN-NIR</b> as a promising platform for early, noninvasive diagnosis of hepatic ischemia and for distinguishing it from reperfusion-related oxidative stress.

Liver regeneration is a complex process involving hepatocyte proliferation and differentiation, which is essential for restoring liver function after liver injury. Hepatocyte repopulation plays a central role in this regenerative process, and extensive research has aimed to elucidate the triggering mechanisms of hepatocyte proliferation as well as the origins of new hepatocytes. Partial hepatectomy, drug-induced liver injuries, and other genetic mouse models have been widely employed to investigate the regenerative machinery of the liver. However, the exact sources of regenerating hepatocytes remain controversial. While substantial evidence supports the model in which pre-existing hepatocytes self-duplicate to replenish the liver, alternative hypotheses suggest that biliary epithelial cells and hepatic progenitor cells also contribute under certain injury conditions. Recently, advanced techniques, including lineage tracing and spatial transcriptomics, have been utilized to track cell lineages and analyze changes in cell composition during liver regeneration, greatly advancing the field. Given that hepatocytes perform the majority of liver functions, understanding the contributing signaling pathways of hepatocyte repopulation is the most critical among the whole process of liver regeneration. Therefore, this review specifically focuses on summarizing current findings in the cellular and molecular mechanisms underlying hepatocyte repopulation during liver regeneration.