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Article Open Access

A 4‑cuproptosis‑related lncRNA theragnostic signature predicts survival and immunotherapy response in patients with lung adenocarcinoma

  • Authors:
    • Lina Lu
    • Yinyin Qin
    • Mingdeng Wang
    • Yanjun Deng
    • Yuansheng Lin
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    Affiliations: Department of Radiation Oncology, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu 215000, P.R. China, Institute of Clinical Medicine Research, Suzhou Research Center of Medical School, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu 215000, P.R. China, Department of Intensive Care Unit, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University, Suzhou, Jiangsu 215000, P.R. China
    Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 3
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    Published online on: October 30, 2025
       https://doi.org/10.3892/mco.2025.2912
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Abstract

Lung adenocarcinoma (LUAD), the most prevalent histological subtype of lung cancer worldwide, is associated with poor survival outcomes. Both cuproptosis and long non‑coding RNAs (lncRNAs) demonstrate significant prognostic value and play emerging roles in LUAD immunotherapy. The aim of the present study was to identify a cuproptosis‑related lncRNA signature for predicting survival and treatment response in patients with LUAD. Cuproptosis‑related lncRNAs were screened from The Cancer Genome Atlas‑LUAD cohort using Pearson correlation analysis (|R|>0.3, P<0.001) with 19 established cuproptosis genes. To establish a prognostic lncRNA signature for LUAD, univariate Cox regression followed by LASSO and multivariate Cox regression analyses were employed. Validation was performed using Kaplan‑Meier survival analysis, principal component analysis, and functional enrichment analysis. A clinical nomogram integrating the signature with clinicopathological features was subsequently developed. The association of the signature with immunotherapy response and chemosensitivity was further assessed. Finally, reverse transcription‑quantitative PCR confirmed the differential expression of cuproptosis‑related lncRNAs in LUAD tissues. The results revealed that a 4‑cuproptosis‑related lncRNA signature (AC026355.2, AP000695.1, ARHGEF26‑AS1 and AP005137.2) was established, demonstrating its utility as an independent prognostic factor for overall survival in patients with LUAD. In addition, the signature effectively differentiates between patients with different responses to immunotherapy. Finally, candidate compounds targeting the signature were identified. In conclusion, this cuproptosis‑related lncRNA signature stratifies LUAD prognosis and immunotherapy response and provides a theragnostic tool for personalized therapy.
View Figures

Figure 1

Identification of
cuproptosis-associated lncRNAs in LUAD. (A) Sankey diagram of the
19 cuproptosis-associated genes and 16,876 lncRNAs from The Cancer
Genome Atlas-LUAD. (B) Heatmap of the correlation between the 19
cuproptosis-associated genes and 4 cuproptosis-associated lncRNAs.
*P<0.05, **P<0.01,
***P<0.001. lncRNA, long non-coding RNA; LUAD, lung
adenocarcinoma.

Figure 2

Construction of
cuproptosis-associated long non-coding RNA signature. (A)
Cross-validation error curve with the tuning parameter log λ. The
optimal model was selected according to the Akaike Information
Criterion (AIC) and 1-SE rule. (B) 10-fold cross-validation
LASSO.

Figure 3

Construction and validation of the
4-lncRNA prognostic signature in The Cancer Genome Atlas-lung
adenocarcinoma cohorts. (A and E) Risk score distribution for
patients in the (A) training cohort (n=360) and (E) test cohort
(n=155). Patients are ordered by risk score (low to high). (B and
F) Survival status scatter plots showing patient survival outcomes
(dead: red; alive: blue) against risk scores in the (B) training
and (F) test cohorts. (C and G) Heatmaps of signature lncRNA
expression (rows: 4 lncRNAs; columns: patients) in the (C) training
and (G) test cohorts. Expression levels are z-score normalized
(red: high; blue: low). (D and H) Kaplan-Meier survival curves
comparing overall survival between high- and low-risk groups in the
(D) training and (H) test cohorts (log-rank P<0.001).

Figure 4

Kaplan-Meier overall survival curves
of the high- and low-risk patients stratified by age, sex and TNM
classification in The Cancer Genome Atlas training and test sets.
(A) Patients with stage I-II. (B) Patients with female. (C)
Patients ≤65 years old. (D) Patients with stage III-IV. (E)
Patients with male. (F) Patients >65 years old.

Figure 5

Principal Component Analysis for the
high- and low-risk patients. (A) Expression profile of 4
cuproptosis-associated lncRNAs. (B) Expression profile 21
cuproptosis-associated genes. (C) Whole-genome expression profile.
(D) The 4 cuproptosis-associated lncRNA signature. Variance
explained by top 3 PCs: (A) Signature=58.7%, (B) Cuproptosis
genes=41.2%, (C) Whole genome=18.3% and (D) Risk model=72.1%.
Separation efficiency calculated as: (Between-group variance/Total
variance) x100.

Figure 6

Long non-coding RNA signature
predicts the tumor immune microenvironment and immunotherapy
response. (A) Infiltration of immune cells. (B) Gene Ontology
annotations. (C) Kyoto Encyclopedia of Genes and Genomes pathways.
(D and E) Waterfall plot of the mutation data of the top 15 genes
with the highest mutation frequency. (F) TIDE scores.
*P<0.05, **P<0.01,
***P<0.001. BP, biological process; MF, molecular
function; CC, cellular component.

Figure 7

TMB analysis. (A) Difference in TMB
between the high- and low-risk groups. (B) Kaplan-Meier OS curves
of patients with a high TMB and a low TMB in high- and low-risk
groups, respectively. (C) Kaplan-Meier OS curves of high- and
low-risk patients stratified by TMB. TMB, tumor mutational burden;
OS, overall survival.

Figure 8

Independence of the Risk score in
prediction of survival outcome of patients with LUAD. (A and B)
Uni- and multivariate Cox regression analyses for the risk score
and clinical features. (C) C-index for the Risk score and clinical
features. (D) ROC curves of the Risk score for 1-, 3- and 5-year
overall survival. (E) Receiver Operating Characteristic curves of
the Risk score and clinical features.

Figure 9

Establishment and validation of
nomogram. (A) Receiver Operating Characteristic curves of the
nomogram for 1-, 3- and 5-year OS. (B) Calibration curve.
*P<0.05, ***P<0.001. OS, overall
survival.

Figure 10

Candidate compounds targeting the
long non-coding RNA signature.
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Spandidos Publications style
Lu L, Qin Y, Wang M, Deng Y and Lin Y: A 4‑cuproptosis‑related lncRNA theragnostic signature predicts survival and immunotherapy response in patients with lung adenocarcinoma. Mol Clin Oncol 24: 3, 2026.
APA
Lu, L., Qin, Y., Wang, M., Deng, Y., & Lin, Y. (2026). A 4‑cuproptosis‑related lncRNA theragnostic signature predicts survival and immunotherapy response in patients with lung adenocarcinoma. Molecular and Clinical Oncology, 24, 3. https://doi.org/10.3892/mco.2025.2912
MLA
Lu, L., Qin, Y., Wang, M., Deng, Y., Lin, Y."A 4‑cuproptosis‑related lncRNA theragnostic signature predicts survival and immunotherapy response in patients with lung adenocarcinoma". Molecular and Clinical Oncology 24.1 (2026): 3.
Chicago
Lu, L., Qin, Y., Wang, M., Deng, Y., Lin, Y."A 4‑cuproptosis‑related lncRNA theragnostic signature predicts survival and immunotherapy response in patients with lung adenocarcinoma". Molecular and Clinical Oncology 24, no. 1 (2026): 3. https://doi.org/10.3892/mco.2025.2912
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Spandidos Publications style
Lu L, Qin Y, Wang M, Deng Y and Lin Y: A 4‑cuproptosis‑related lncRNA theragnostic signature predicts survival and immunotherapy response in patients with lung adenocarcinoma. Mol Clin Oncol 24: 3, 2026.
APA
Lu, L., Qin, Y., Wang, M., Deng, Y., & Lin, Y. (2026). A 4‑cuproptosis‑related lncRNA theragnostic signature predicts survival and immunotherapy response in patients with lung adenocarcinoma. Molecular and Clinical Oncology, 24, 3. https://doi.org/10.3892/mco.2025.2912
MLA
Lu, L., Qin, Y., Wang, M., Deng, Y., Lin, Y."A 4‑cuproptosis‑related lncRNA theragnostic signature predicts survival and immunotherapy response in patients with lung adenocarcinoma". Molecular and Clinical Oncology 24.1 (2026): 3.
Chicago
Lu, L., Qin, Y., Wang, M., Deng, Y., Lin, Y."A 4‑cuproptosis‑related lncRNA theragnostic signature predicts survival and immunotherapy response in patients with lung adenocarcinoma". Molecular and Clinical Oncology 24, no. 1 (2026): 3. https://doi.org/10.3892/mco.2025.2912
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