Cancer Commun (Lond). 2026 Sep 11;46:0048. doi: 10.34133/cancomm.0048. eCollection 2026.

ABSTRACT

Background: Cancer cells frequently acquire adaptive resistance to targeted therapies; however, strategies capable of concurrently overcoming treatment tolerance and reactivating cell death pathways are currently lacking. Here, we investigated the dual role of ferredoxin 1 (FDX1) in modulating both multikinase inhibitor (MKI) sensitivity and cuproptosis susceptibility in hepatocellular carcinoma (HCC), and sought to develop a therapeutic approach for reversing resistance. Methods: HCC models, both in vitro and in vivo, were employed to investigate the role of FDX1 in MKI resistance and cuproptosis evasion. Polysome profiling, SunTag translation reporters, CRISPR-Cas9 mutagenesis, and mass spectrometry were employed to delineate the underlying mechanisms. A codelivery nanoliposome system was engineered and tested in orthotopic HCC models. Results: Prolonged exposure to MKIs led to the down-regulation of FDX1 protein levels, resulting in MKI resistance and cuproptosis tolerance in HCC both in vitro and in vivo. Mechanistically, we found that MKIs inactivated protein kinase B (PKB, also known as AKT)-mechanistic target of rapamycin (mTOR) signaling, thereby suppressing the SET and MYND domain-containing protein 2 (SMYD2)-mediated methylation of YTH domain family protein 1 (YTHDF1) at lysine 515 (K515). Hypomethylated YTHDF1 was degraded via next to BRCA1 gene 1 protein (NBR1)-dependent autophagy, leading to the repression of N6-methyladenosine modification-dependent translation of FDX1 mRNA. FDX1 deficiency drove MKI resistance by reactivating AKT survival signaling while impairing cuproptosis through reduced divalent copper ions (Cu²⁺) to monovalent copper ions (Cu⁺) conversion and the loss of protein lipoylation. Additionally, restoring FDX1 expression through NBR1 knockdown or YTHDF1 overexpression overcame MKI resistance and resensitized HCC cells to cuproptosis. Finally, a nanoliposomal system, super cuproptosis detonator liposome, designed for the codelivery of NBR1 small interfering RNA, a copper ionophore, and sorafenib restored FDX1-dependent cuproptosis and exhibited marked anti-HCC efficacy, suppressing HCC growth in vivo. Conclusions: MKIs suppressed SMYD2-mediated YTHDF1 methylation at K515 via the inactivation of AKT-mTOR signaling. This led to the inhibition of FDX1 translation, resulting in AKT signaling reactivation and protein lipoylation impairment, effects that contributed to both MKI resistance and cuproptosis tolerance in HCC. Overcoming MKI resistance and resensitizing cells to cuproptosis by targeting NBR1-mediated YTHDF1 degradation using a nanoliposomal codelivery system represents a promising strategy for HCC treatment.

PMID:42729649 | PMC:PMC13562797 | DOI:10.34133/cancomm.0048

J Thorac Dis. 2026 Aug 31;18(8):883. doi: 10.21037/jtd-2026-0807. Epub 2026 Jul 21.

ABSTRACT

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition not fully captured by spirometry. Quantitative computed tomography (QCT) enables objective characterization of emphysema, airway remodeling, and other structural abnormalities, playing key roles in early recognition, phenotyping, and prognosis. Despite growing literature in this field, no comprehensive bibliometric synthesis has mapped the intellectual structure, collaborative networks, or thematic evolution of QCT research in COPD. This study aims to fill this gap by providing a structured overview of the field over the past two decades.

METHODS: A systematic search was performed in the Web of Science Core Collection (WoSCC) using the topic formula: TS=(("quantitative computed tomography" OR "quantitative CT" OR "QCT" OR "CT quantification" OR "quantitative CT assessment") AND ("chronic obstructive pulmonary disease" OR "COPD" OR "chronic obstructive pulmonary disease*")). Publications from 2005 to 2025 were included, limited to English original articles and reviews. Titles and abstracts were independently screened by two reviewers; studies not primarily focusing on QCT-based quantitative analysis in COPD were excluded. Disagreements were resolved through discussion. Bibliometric and visual analyses were conducted using CiteSpace 6.4.R1, VOSviewer 1.6.19, and the R package bibliometrix.

RESULTS: A total of 300 publications (279 original articles, 21 reviews) were included. The United States was the leading contributor in overall output and international collaboration. The University of Iowa was the most productive institution, Hoffman EA was the most prolific author, and the International Journal of Chronic Obstructive Pulmonary Disease was the most productive journal. Keyword and thematic analyses revealed a clear evolutionary trajectory: early research (2005-2012) focused on technical quantification of emphysema and airway abnormalities; a transitional phase (2013-2018) emphasized "phenotypes" and disease heterogeneity; and the recent period (2019-2025) has seen rising attention to prognostic evaluation, mortality prediction, and artificial intelligence-assisted analysis.

CONCLUSIONS: This study confirms a shift from morphologic quantification toward clinically actionable imaging biomarkers. However, the existing literature suffers from several critical gaps: lack of standardized acquisition and analysis protocols, predominance of cross-sectional designs, and insufficient external validation of artificial intelligence models. Future research should prioritize multicenter prospective validation, integration with multi-omics data for endotyping, and development of open-source automated pipelines to facilitate clinical translation.

PMID:42724634 | PMC:PMC13559334 | DOI:10.21037/jtd-2026-0807