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The dual role of the crosstalk between autophagy and ferroptosis in lung cancer treatment: Advances in mechanisms and therapeutic strategies (Review)

  • Authors:
    • Yingying Zhang
    • Ruxin Shen
  • View Affiliations / Copyright

    Affiliations: Department of Tuberculosis, Affiliated Nantong Hospital of Shanghai University, Nantong, Jiangsu 226000, P.R. China, Qingdao Medical College, Qingdao University, Qingdao, Shandong 266000, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 108
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    Published online on: March 2, 2026
       https://doi.org/10.3892/ijmm.2026.5779
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Abstract

The interaction between autophagy and ferroptosis has resulted in the identification of novel approaches for the treatment of lung cancer (LC). The two processes are closely interconnected via three core regulatory modes: Negative regulation, positive regulation and feedback regulation, thereby forming a complex and context‑dependent regulatory network. Within the context of LC progression, the interaction between autophagy and ferroptosis exhibits a dual role. On one hand, it promotes LC development by enabling cancer cell survival in adverse microenvironments, remodeling metabolic pathways and orchestrating the tumor microenvironment to facilitate immune evasion. On the other hand, it can suppress LC by removing damaged cellular components, inducing ferroptosis, and boosting immune surveillance and clearance of cancer cells. Consequently, therapeutic strategies for LC are continuously evolving. In the field of pharmacotherapy, traditional agents such as chloroquine and its derivatives are being repurposed with subtype‑dependent efficacy, and their antitumor activity can be potentiated via nanoparticle delivery systems. When combined with ferroptosis inducers or other drugs, these agents can augment therapeutic efficacy and surmount drug resistance. Current research and development efforts are focused on small‑molecule compounds that target key nodes in autophagy‑ferroptosis crosstalk. Moreover, combination therapy represents a central focus of research. When combined with chemotherapy, radiotherapy, targeted therapy and immunotherapy, this combination approach shows potential for synergistic efficacy. However, current research faces several challenges, including the complexity of regulatory mechanisms and inter‑individual variability. Most therapeutic strategies remain in the preclinical research phase and the synergistic mechanisms of combination therapies are not yet fully elucidated. Comprehensive investigations into the molecular processes, coupled with the application of multi‑omics technologies, are crucial for clarifying the regulatory network. The development of precise biomarkers, along with the integration of artificial intelligence and big data analytics, is essential to accelerate the advancement of novel drugs and therapeutic strategies, with the ultimate goal of improving the prognosis for patients with LC.
View Figures

Figure 1

Mechanisms of autophagy and
ferroptosis, and the regulatory mechanisms between them. The figure
was created by Figdraw (www.figdraw.com). RSL3, RAS selective lethal 3; GPX4,
glutathione peroxidase 4; TMEM164, transmembrane protein 164; ATG5,
autophagy related 5; NCOA4, nuclear receptor coactivator 4;
LAPTM4B, lysosome associated protein transmembrane 4B; SLC7A11,
solute carrier family 7 member 11; IGF2BP1, insulin-like growth
factor 2 mRNA binding protein 1; GSH, glutathione; UPF1,
up-frameshift protein 1; GAS5, growth arrest specific 5; RGS20,
regulator of G protein signaling 20; SCD1, stearoyl-CoA desaturase
1; FGF21, fibroblast growth factor 21; ROS, reactive oxygen
species; BNIP3, BCL2 interacting protein 3; NIX, NIP3-like protein
X; COX7A1, cytochrome c oxidase subunit 7A1; NRF2, nuclear
factor, erythroid 2 like 2; ULK1, Unc-51 like kinase 1; mTOR,
mechanistic target of rapamycin.

Figure 2

Mechanisms of the crosstalk
regulation between autophagy and ferroptosis in lung cancer and
lung cancer pharmacotherapy. The figure was created by Figdraw
(www.figdraw.com). LDHB, lactate dehydrogenase B;
GSH, glutathione; CO, carbon monoxide; PAB, pseudolaric acid B;
ROS, reactive oxygen species; Cory, corynoxine; PP2A, protein
phosphatase 2A; ULK1, unc-51 like kinase 1; SCD1, stearoyl-CoA
desaturase 1; SND1, staphylococcal nuclease and tudor domain
containing 1; PDCD4, programmed cell death 4; CA, carnosic acid;
lncRNA, long non-coding RNA; p-mTOR, phosphorylated mechanistic
target of rapamycin; miR-139, microRNA-139; NRF2, nuclear factor,
erythroid 2 like 2; DTX2, deltex E3 ubiquitin ligase 2; NCOA4,
nuclear receptor coactivator 4.

Figure 3

Mechanisms of autophagy and
ferroptosis in lung cancer gene therapy, targeted therapy and
immunotherapy. The figure was created by Figdraw (www.figdraw.com). GSH, glutathione; ROS, reactive
oxygen species; PAM, plasma-activated medium; FSP1, ferroptosis
suppressor protein 1; NRF2, nuclear factor, erythroid 2 like 2;
PHKG2, phosphorylase kinase catalytic subunit γ2; DDX24, DEAD-box
helicase 24; ACSL6, long-chain acyl-CoA synthase 6; COL, collagen;
AATK, apoptosis-associated tyrosine kinase; ShtIX,
S-3-hydroxy-7',2',4'-trimethoxyisoflavone; MAFF, MAF bZIP
transcription factor F; YAP, Yes-associated protein; SLC7A11,
solute carrier family 7 member 11; VDAC, voltage-dependent anion
channel.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang Y and Shen R: The dual role of the crosstalk between autophagy and ferroptosis in lung cancer treatment: Advances in mechanisms and therapeutic strategies (Review). Int J Mol Med 57: 108, 2026.
APA
Zhang, Y., & Shen, R. (2026). The dual role of the crosstalk between autophagy and ferroptosis in lung cancer treatment: Advances in mechanisms and therapeutic strategies (Review). International Journal of Molecular Medicine, 57, 108. https://doi.org/10.3892/ijmm.2026.5779
MLA
Zhang, Y., Shen, R."The dual role of the crosstalk between autophagy and ferroptosis in lung cancer treatment: Advances in mechanisms and therapeutic strategies (Review)". International Journal of Molecular Medicine 57.5 (2026): 108.
Chicago
Zhang, Y., Shen, R."The dual role of the crosstalk between autophagy and ferroptosis in lung cancer treatment: Advances in mechanisms and therapeutic strategies (Review)". International Journal of Molecular Medicine 57, no. 5 (2026): 108. https://doi.org/10.3892/ijmm.2026.5779
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang Y and Shen R: The dual role of the crosstalk between autophagy and ferroptosis in lung cancer treatment: Advances in mechanisms and therapeutic strategies (Review). Int J Mol Med 57: 108, 2026.
APA
Zhang, Y., & Shen, R. (2026). The dual role of the crosstalk between autophagy and ferroptosis in lung cancer treatment: Advances in mechanisms and therapeutic strategies (Review). International Journal of Molecular Medicine, 57, 108. https://doi.org/10.3892/ijmm.2026.5779
MLA
Zhang, Y., Shen, R."The dual role of the crosstalk between autophagy and ferroptosis in lung cancer treatment: Advances in mechanisms and therapeutic strategies (Review)". International Journal of Molecular Medicine 57.5 (2026): 108.
Chicago
Zhang, Y., Shen, R."The dual role of the crosstalk between autophagy and ferroptosis in lung cancer treatment: Advances in mechanisms and therapeutic strategies (Review)". International Journal of Molecular Medicine 57, no. 5 (2026): 108. https://doi.org/10.3892/ijmm.2026.5779
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