Background and Aims: Hyperlipidemia has been extensively recognized as a high-risk factor for non-alcoholic steatohepatitis (NASH); however, clinical susceptibility to NASH is highly heterogeneous. The key controller(s) of NASH susceptibility in patients with hyperlipidemia have not yet been elucidated. Here, we aimed to reveal the key regulators of NASH in patients with hyperlipidemia and to explore its role and underlying mechanisms. Approach and results: To identify the predominant suppressors of NASH in the setting of hyperlipidemia, we collected liver biopsy samples from patients with hyperlipidemia, with or without NASH, and performed RNA-seq analysis. Notably, decreased LIM domain only 7 (LMO7) expression robustly correlated with the occurrence and severity of NASH. Although overexpression of LMO7 effectively blocked hepatic lipid accumulation and inflammation, LMO7 deficiency in hepatocytes greatly exacerbated diet-induced NASH progression. Mechanistically, lysine 48 (K48)-linked ubiquitin-mediated proteasomal degradation of tripartite motif 47 (TRIM47) and subsequent inactivation of the JNK/p38 MAPK cascade are required for the protective function of LMO7 in NASH. Conclusions: These findings provide proof-of-concept evidence supporting LMO7 as a robust suppressor of NASH in the context of hyperlipidemia, indicating that targeting the LMO7-TRIM47 axis is a promising therapeutic strategy for NASH. Export

This study aims to investigate the potential prognostic value of albumin-bilirubin (ALBI) score in breast cancer patients with liver metastasis after surgery. This was a retrospective study of 178 breast cancer patients with liver metastasis after surgery. ALBI score was calculated by the following formula: (log10 bilirubin × 0.66) − (albumin × 0.085). The optimal cutoff value of ALBI score was assessed by X-tile. The clinical influence of ALBI score on survival outcomes using Kaplan-Meier method, Log-rank test, Cox proportional hazards regression model. The calibration curves, decision curve analysis and time-dependent ROC curve were used to assess the predictive performance of the nomogram's models. The classifications of 178 breast cancer patients with liver metastasis after surgery were as follows: low ALBI score group (＜−3.36) vs. high ALBI score group (≥−3.36). The Cox proportional hazards regression model indicated that ALBI score was a potential predictor. Kaplan-Meier survival curve performed that the median disease free survival (p = 0.0029) and overall survival (p＜0.0001) in low ALBI score group were longer than in high ALBI score group. The ALBI-based nomograms had good predictive performance. The ALBI score has high prognostic ability for survival time in breast cancer with liver metastasis after surgery. These models will be valuable in discriminating patients at high risks of liver metastasis.

Non-alcoholic fatty liver disease (NAFLD) is expected to become the leading risk factor for liver cancer, surpassing viral hepatitis. Unlike viral hepatitis-related hepatocellular carcinoma (HCC), the role of excessive nutrient supply in steatotic HCC is not well understood, hindering effective prevention and treatment strategies. Therefore, it is crucial to identify key molecules in the pathogenesis of steatotic HCC, investigate changes in metabolic reprogramming due to excessive fatty acid (FA) supply, understand its molecular mechanisms, and find potential therapeutic targets. Trans-species transcriptome analysis identified Ring Finger Protein 5 (RNF5) as a critical regulator of steatotic HCC. RNF5 upregulation is associated with poor prognosis in steatotic HCC compared to canonical HCC. In vitro and in vivo studies showed that RNF5 exacerbates HCC in the presence of additional FA supply. Lipidomics and transcriptome analyses revealed that RNF5 significantly increases carnitine palmitoyltransferase 1A (CPT1A) mRNA levels and is positively correlated with fatty acid oxidation (FAO). Protein interaction analysis demonstrated that RNF5 promotes K63-type ubiquitination of insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1), enhancing CPT1A mRNA stabilization through m6A modification. Additionally, peroxisome proliferator-activated receptor gamma (PPARγ) was found to activate RNF5 expression specifically in HCC cells. Mechanistically, excessive exogenous FAs reorganize FA metabolism in HCC cells, worsening steatotic HCC via the PPARγ-RNF5-IGF2BP1-CPT1A axis. This study highlights a distinct FA metabolism pattern in steatotic HCC, providing valuable insights for potential therapeutic targets.