Correlation between ARD1 expression and clinicopathologic parameters in HCC patients

PABPC1 Ki67 acetylation enhances its binding affinity for GCLC mRNA

Ki67 acetylation promotes PABPC1 cytosolic retention

Osteoarthritis (OA) is a prevalent age-related degenerative joint disorder characterized by dysregulation of metabolism. While several studies have examined the metabolic changes in OA, there exists a lack of a comprehensive retrospective analysis of its current development, research hotspots, and future trends. In this study, we employed bibliometric approaches to retrospectively review the development, mechanisms, and future trends of metabolic changes in OA. We utilized VOSviewer software to quantitatively and visually depict: (a) annual temporal trends in literature and citation counts; (b) national/regional publications and collaborations; (c) institutional and author contributions; (d) journal contributions and relevance; (e) analysis of research hotspots and directions through keywords. By analyzing keywords and research hotspots, we systematically illustrated the influential factors of metabolic changes in OA, including inflammation, apoptosis, oxidative stress, and autophagy. Conclusively, the research field of metabolic changes in OA is rapidly expanding, and we aim to provide a more comprehensive and insightful perspective for targeting metabolic disorders in OA.

ARD1 regulates GCLC mRNA stability

SIRT1 and SIRT7 mediate PABPC1 deacetylation

Aberrant upregulation of the intracellular antioxidant glutathione (GSH) is implicated in promoting tumor proliferation, inducing drug resistance, and inhibiting ferroptosis across various malignancies, including hepatocellular carcinoma (HCC). Targeting the mechanism underlying GSH upregulation in HCC could represent a therapeutic strategy to improve patient outcomes. In this study, we employed a genome-wide CRISPR/Cas9 screen and targeted metabolomics to identify the acetyltransferase ARD1 as a pivotal facilitator of de novo GSH synthesis in HCC. Notably, ARD1 upregulation was positively correlated with elevated GSH levels and poor prognosis in patients with HCC. In vivo and in vitro functional assays revealed that ARD1 promoted HCC cell proliferation and inhibited ferroptosis in a GSH-dependent manner. LC/MS-MS-based stable isotope labeling revealed that ARD1 increased GSH levels by stabilizing γ-glutamylcysteine ligase catalytic (GCLC) subunit mRNA, which was mediated by the RNA-binding protein PABPC1. Mechanistically, ARD1 acetylated PABPC1 at Ki67, augmenting its cytoplasmic retention by disrupting PABPC1-importin α7 complex formation. Cytoplasmic PABPC1 then interacted with eIF4G to collaboratively stabilize GCLC mRNA, preventing its degradation, increasing GSH synthesis, and ultimately conferring ferroptosis resistance in HCC cells. Furthermore, oxidative stress induced by hydrogen peroxide suppressed ARD1 ubiquitination and degradation, thereby promoting PABPC1 cytoplasmic translocation and inducing GCLC expression. ARD1 suppression promoted sorafenib-mediated ferroptosis in xenografts derived from patients with HCC tumors with high ARD1 and GCLC expression. Overall, this research uncovers an oxidative stress-ARD1-PABPC1-GCLC axis with a crucial role in GSH metabolic reprogramming and ferroptosis regulation in HCC and reveals a strategy for ferroptosis-based targeted therapy for HCC. SIGNIFICANCE:The acetyltransferase ARD1 promotes hepatocellular carcinoma progression, inhibits ferroptosis by upregulating GCLC to facilitate de novo synthesis of glutathione, and can be targeted to improve sorafenib efficacy.

Genome-scale CRISPR-Cas9 screen identified ARD1 as a key regulator of GSH synthesis

PABPC1 mediates the mRNA stabilization effects of ARD1 on GCLC

Nrf2 and ARD1 demonstrate a synergistic effect in inhibiting ferroptosis in HCC

Hepatocellular carcinoma (HCC) poses a significant global health burden, with escalating incidence rates and substantial mortality. The predominant etiological factors include liver cirrhosis (LC) and chronic hepatitis B infections (CHB). Surveillance primarily relies on ultrasound and Alpha-fetoprotein (AFP), yet their efficacy, particularly in early HCC detection, is limited. Hence, there is a critical need for accurate non-invasive biomarkers to enhance surveillance and early diagnosis.Extracellular vesicles (EVs) hold promises as stable carriers of signaling molecules, offering potential in tumor diagnosis. Our study developed a novel tidal microfluidic chip for label-free EV isolation, enabling rapid and efficient enrichment from small plasma volumes. Through transcriptome sequencing and single-cell analysis, we identified HMMR and B4GALT2 as promising HCC-associated biomarkers in EVs.In a comprehensive clinical evaluation, bi-mRNAs in EVs exhibited superior diagnostic performance over AFP, particularly in distinguishing early-stage HCC or AFP-negative cases from high-risk individuals (CHB/LC). Notably, our study demonstrated the potential of bi-mRNAs to complement imaging examinations, enabling early detection of HCC lesions.In conclusion, the tidal microfluidic chip offers a practical solution for EV isolation, with the integration of EV-based biomarkers presenting opportunities for improved early detection and management of HCC in clinical practice.