Integrated transcriptomic profiling identifies a clinically adverse iron-autophagy imbalance state in neuroblastoma.

@article{zhang2026integrated,
  title = {{Integrated transcriptomic profiling identifies a clinically adverse iron-autophagy imbalance state in neuroblastoma.}},
  author = {Li Zhang and Xiaomeng Wang and Zhanbo Wu and Yinan Dong and Runmei Li},
  journal = {Translational pediatrics},
  year = {2026},
  month = sep,
  doi = {10.21037/tp-2026-0827},
  url = {https://europepmc.org/article/MED/42996735},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - Integrated transcriptomic profiling identifies a clinically adverse iron-autophagy imbalance state in neuroblastoma.
AU  - Li Zhang
AU  - Xiaomeng Wang
AU  - Zhanbo Wu
AU  - Yinan Dong
AU  - Runmei Li
PY  - 2026
DA  - 2026/09/30
JO  - Translational pediatrics
DO  - 10.21037/tp-2026-0827
UR  - https://europepmc.org/article/MED/42996735
AB  - Neuroblastoma is characterized by marked molecular heterogeneity, and additional biological states contributing to aggressive disease remain incompletely defined. Ferritinophagy-related genes connect ferritin turnover, intracellular iron regulation, and autophagy-associated processes, but whether they delineate clinically relevant iron-autophagy transcriptional states in neuroblastoma is unclear. We aimed to identify clinically relevant iron-autophagy transcriptional states in neuroblastoma and assess their cross-cohort transferability, cellular distribution, and treatment-associated differences. We integrated bulk transcriptomic, single-cell RNA-sequencing, and region-of-interest (ROI)-level GeoMx Digital Spatial Profiling datasets. Ferritinophagy-related genes were used as an entry point for unsupervised classification in the GSE62564 discovery cohort, followed by construction of a locked 34-gene centroid classifier and a continuous C1-associated axis, which were projected without gene reselection or refitting into three independent bulk cohorts. A four-gene iron-autophagy imbalance index (IA4) was derived from opposing iron-handling and autophagy-associated transcriptional components. Single-cell and spatial analyses assessed malignant-cell expression, treatment-associated differences within malignant cells, and clinical-risk associations. Two transcriptional states were identified. In GSE62564, C1 comprised 180 of 498 tumors and was associated with inferior overall survival (OS) [univariable hazard ratio (HR), 16.51; 95% confidence interval (CI): 9.52-28.63] and event-free survival (EFS) (HR, 4.24; 95% CI: 3.13-5.74); at 5 years, C1 was associated with a 1.45-year loss of restricted mean OS (95% CI: 1.18-1.72). The associations remained significant after adjustment for age, stage, and MYCN status (OS HR, 5.03; 95% CI: 2.53-9.99; EFS HR, 2.00; 95% CI: 1.30-3.08). In three independent bulk cohorts, a 1-standard deviation (SD) increase in the continuous C1 score was associated with inferior OS (HR range, 1.58-2.44; all P<0.001). C1 tumors showed coordinated malignant and iron-autophagy-associated programs. IA4, defined from TFRC, PCBP1, PINK1, and ATG16L1, correlated with the continuous C1 axis in 34 pretreatment tumor ROIs (Spearman rho =0.64, P=4.3×10-5) and remained robust in leave-one-gene-out analyses. In 22 paired longitudinal donors, the malignant-cell weighted C1 score decreased after treatment (P=0.002), and the cycle-residual component remained lower after adjustment for S-phase and G2/M activity (P=0.01). Using ferritinophagy-related genes as a discovery framework, this study identifies a clinically adverse iron-autophagy imbalance state in neuroblastoma and provides a compact transcriptional representation through IA4. The findings establish a framework for future functional investigation without implying direct measurement of ferritinophagic flux, intracellular iron, or ferroptosis sensitivity.
SN  - 2224-4336
SN  - 2224-4344
ER  -