Clinical and Molecular Hepatology最新文献

Background/aims: The association between aspirin use and hepatocellular carcinoma (HCC) risk in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study evaluated the effect of aspirin on HCC development in MASLD patients using Korean National Health Insurance Service (NHIS) and UK Biobank (UKB) databases.

Methods: A retrospective cohort analysis was conducted using the NHIS database with a 3-year landmark design. Baseline characteristics were balanced using inverse probability of treatment weighting (IPTW) and 1:3 propensity score matching (PSM). Additionally, Mendelian randomization analysis was performed in the UKB cohort using a genomic risk score (GRS) for salicylic acid, based on genetic variants related to aspirin metabolism, as a proxy for aspirin use.

Results: In the NHIS cohort, 6,584,155 eligible patients were included, of whom 1,723,435 had MASLD. After PSM, aspirin use was associated with a significantly lower risk of HCC compared to no aspirin use, in both the overall population (adjusted subdistribution hazard ratio [ASHR]=0.86; 95% confidence interval [CI] 0.78-0.95; P=0.002) and MASLD group (ASHR=0.86; 95% CI 0.75-0.99; P=0.036). Similar results were reproduced in the IPTW population and several sensitivity and subgroup analyses. In the UKB cohort, individuals in the top 95% of GRS had a significantly lower risk of HCC compared to those in the bottom 5%, in both the overall population (ASHR=0.61; 95% CI 0.39-0.95; P=0.028) and MASLD group (ASHR=0.47; 95% CI 0.29-0.76; P=0.002).

Conclusions: Findings from both population-based and genetic analyses suggest a possible protective association between aspirin use and HCC in patients with MASLD, which warrants further validation.

Background/aims: Endoplasmic reticulum (ER) stress in hepatocytes plays a causative role in alcohol-associated liver disease (ALD). The incomplete inhibition of ER stress by targeting canonical ER stress sensor proteins suggests the existence of noncanonical ER stress pathways in ALD pathology. This study aimed to delineate the role of RAB25 in ALD and its regulatory mechanism in noncanonical ER stress pathways.

Methods: RAB25 activation was examined in liver samples from ALD patients and ethanol-fed mice. The interaction between RAB25 and GCN1 was confirmed through mass spectrometry and co-immunoprecipitation (Co-IP) assays in vitro. The role of RAB25/GCN1 in promoting noncanonical ER stress in ALD was assessed both in vitro and in vivo.

Results: RAB25 expression was upregulated and specifically accumulated on the ER in ALD. Mass spectrometry and Co-IP assays confirmed that RAB25 interacts with GCN1, thereby activating a noncanonical ER stress pathway that facilitates ALD progression. Further analysis revealed that RAB25 interaction with GCN1 inhibits K33-ubiquitination-mediated degradation of GCN1, promotes GCN2 phosphorylation, and subsequently activates ATF4-mediated ER stress. This activation modulates lipid metabolism, mitochondrial function, and inflammation, thereby facilitating ALD progression. Knockdown of RAB25 in hepatocytes inhibited ER stress activation and mitigated associated mitochondrial dysfunction, excessive lipid synthesis, and the exaggerated inflammatory response in an ALD model.

Conclusions: Our findings demonstrate a causal role for RAB25-GCN1 signaling in activating the ER stress pathway, which contributes to ALD progression. This pathway may provide a proof-of-concept target for treating ALD and associated metabolic disorders.