Background/Aims Dysregulated cholesterol metabolism is a hallmark of hepatocellular carcinoma (HCC) that drives tumor initiation and progression. However, clinical targeting of cholesterol metabolism has yielded limited benefits due to stringent feedback in tumor cells. Identifying a central mediator capable of restoring cholesterol homeostasis within the cell’s intrinsically fine-tuned regulatory framework is urgently needed.
Methods We integrated a proteomic dataset from patients with cholesterol-dysregulated HCC into a global cholesterol metabolic regulatory network to identify potential therapeutic targets for disrupted cholesterol homeostasis. The prognostic significance of the candidate targets was further validated in an independent cohort through immunohistochemistry. Functional and mechanistic studies were conducted in vitro using HCC cell lines and in vivo using mouse models. The pharmacological efficacy of the candidate agent was evaluated in both subcutaneous and orthotopic HCC mouse models.
Results ER lipid raft-associated 1 (ERLIN1), a pivotal regulator of cholesterol metabolism reprogramming, was identified as an independent favorable prognostic indicator in HCC. ERLIN1 constrains HCC progression both in vitro and in vivo by stabilizing the INSIG1–SCAP–SREBP2 axis and maintaining the metabolic balance of intracellular cholesterol. Under hypoxia, impaired factor-inhibiting hypoxia-1-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 enhances ASB11-mediated ERLIN1 degradation. Pharmacological targeting of this axis using zoledronic acid (ZoA) attenuated HCC progression by weakening the ASB11–ERLIN1 interaction and restoring cholesterol homeostasis.
Conclusions ERLIN1 represents a druggable metabolic vulnerability in cholesterol-dysregulated HCC. Targeting the ASB11–ERLIN1 axis with the clinically approved ZoA reestablishes cholesterol homeostasis and offers a promising therapeutic strategy to overcome the current limitations of cholesterol-targeted HCC therapies.
Background/Aims The role of reactivation of human cytomegalovirus (HCMV) in determining outcomes of cirrhotic patients with acute decompensation (AD) is unknown. We aimed to investigate HCMV incidence and potential correlation with hepatic outcomes in AD patients.
Methods Two prospective multicentre cohorts with AD patients were investigated. Patients in cohort 1 were recruited from 4 centres, while patients in cohort 2 were randomly selected from a second multicentre cohort. HCMV reactivation was established with quantitative real-time polymerase chain reaction assay in seropositive patients.
Results HCMV reactivation was found in 35 patients from cohort 1 (n=722) and 14 from cohort 2 (n=291), with an incidence of 4.8% in both cohorts. Bacterial infection and liver failure were independently correlated with HCMV reactivation. HCMV reactivation was an independent predictor of 90-day mortality. Among bacterial infection populations in these two cohorts, patients with HCMV reactivation had worse prognosis compared to those without. Incidence of acute-on-chronic liver failure (ACLF) was higher in patients with HCMV reactivation compared to those without and was also independently correlated with development of ACLF. In a total of 49 HCMV reactivation cases, 8 patients were treated with ganciclovir, in whom a significantly lower 90-day mortality compared with those not treated was observed. All 3 patients who underwent liver transplantation with reactivation of HCMV died.
Conclusions In AD patients, HCMV reactivation was common, especially in those with bacterial infection or liver failure, and they were more prone to having ACLF and 90‑day mortality. The data propose the need for active surveillance for HCMV infection in AD patients.
Background/Aims Metabolic dysfunction-associated steatohepatitis (MASH) is an unmet clinical challenge due to the rapid increased occurrence but lacking approved drugs. Autophagy-related protein 16-like 1 (ATG16L1) plays an important role in the process of autophagy, which is indispensable for proper biogenesis of the autophagosome, but its role in modulating macrophage-related inflammation and metabolism during MASH has not been documented. Here, we aimed to elucidate the role of ATG16L1 in the progression of MASH.
Methods Expression analysis was performed with liver samples from human and mice. MASH models were induced in myeloid-specific Atg16l1-deficient and myeloid-specific Atg16l1-overexpressed mice by high-fat and high-cholesterol diet or methionine- and choline-deficient diet to explore the function and mechanism of macrophage ATG16L1 in MASH.
Results Macrophage-specific Atg16l1 knockout exacerbated MASH and inhibited energy expenditure, whereas macrophage-specific Atg16l1 transgenic overexpression attenuated MASH and promotes energy expenditure. Mechanistically, Atg16l1 knockout inhibited macrophage lipophagy, thereby suppressing macrophage β-oxidation and decreasing the production of 4-hydroxynonenal, which further inhibited stimulator of interferon genes(STING) carbonylation. STING palmitoylation was enhanced, STING trafficking from the endoplasmic reticulum to the Golgi was promoted, and downstream STING signaling was activated, promoting proinflammatory and profibrotic cytokines secretion, resulting in hepatic steatosis and hepatic stellate cells activation. Moreover, Atg16l1-deficiency enhanced macrophage phagosome ability but inhibited lysosome formation, engulfing mtDNA released by pyroptotic hepatocytes. Increased mtDNA promoted cGAS/STING signaling activation. Moreover, pharmacological promotion of ATG16L1 substantially blocked MASH progression.
Conclusions ATG16L1 suppresses MASH progression by maintaining macrophage lipophagy, restraining liver inflammation, and may be a promising therapeutic target for MASH management.
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