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

Advanced hepatocellular carcinoma (HCC) is characterized by poor prognosis, primarily due to limited therapeutic options and resistance to treatment. Although the combination of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has shown promising potential, the underlying mechanisms remain inadequately understood. Here, serine/threonine‐specific protein phosphatase (PP1A) is upregulated in Lenvatinib‐resistant HCC cells and correlates with poor prognosis. Functional experiments revealed that PP1A promotes HCC progression both in vitro and in vivo. Transcriptomic analysis and ferroptosis metabolite profiling (e.g., ROS, Fe ² ⁺, lipid‐ROS, and GSH) demonstrated that PP1A inhibits Lenvatinib‐induced ferroptosis by dephosphorylating Keap1 at site 104. This disruption of the Keap1‐Nrf2 interaction enhances the transcription of ferroptosis‐related markers and immune checkpoint PD‐L1. Notably, single‐cell sequencing and co‐culture experiments revealed that PP1A knockdown alleviates T cell exhaustion and immune evasion, thereby improving antitumor immunity. In vivo experiments further demonstrated that PP1A knockdown significantly enhances the efficacy of Lenvatinib‐ICIs combination therapy. Overall, our findings highlight PP1A as a critical regulator of ferroptosis and antitumor immunity, suggesting its potential as a predictive biomarker and therapeutic target for improving outcomes in advanced HCC.

Purpose Metabolic reprogramming, particularly the Warburg effect, plays a crucial role in the onset and progression of tumors. The ubiquitin-conjugating enzyme E2 Q2 (UBE2Q2) has been identified overexpressed in hepatocellular carcinoma (HCC). Our aim was to determine if UBE2Q2 plays a role in regulating glycolysis, contributing to the carcinogenesis of HCC. Methods Bioinformatics analysis, western blot and qPCR were used to detect the expression of UBE2Q2. Functional experiments, proteomics analysis and subcutaneous tumors were constructed to find the biological function of UBE2Q2 in HCC. Co-immunoprecipitation, western blot and ubiquitination assays were used to identify the mechanisms involved. Results We found a significant association between high UBE2Q2 expression and poor prognosis in HCC patients. Functionally, UBE2Q2 was shown to advance tumor progression in HCC through both in vitro assays and in vivo assessments. Proteomics analysis and glycolysis stress tests corroborated an increase in glycolytic activity due to UBE2Q2. Our findings reveal that UBE2Q2 augments glycolysis by boosting the transcription levels of hypoxia-inducible factor 1α (HIF1α), primarily through the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. At the molecular level, UBE2Q2 interaction with baculoviral IAP repeat-containing 2 (cIAP1) orchestrates the K63-linked ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1), which in turn, activates the NF-κB signaling pathway. Conclusions Our investigation reveals that UBE2Q2 regulates the glycolysis in HCC through modulation of the NF-κB/HIF1α signaling pathway, pinpointing UBE2Q2 as a promising therapeutic target for the disease. Graphical abstract