ORIGINAL RESEARCH article
Front. Oncol.
Sec. Molecular and Cellular Oncology
This article is part of the Research TopicInnovative Methods, Models and Technologies Shaping the Path to Cancer Cures by 2035View all articles
Integrative Modeling of FOXO-Mediated Autophagy in NSCLC: Linking cGAS-STING Signaling to IL-6 Dynamics
Provisionally accepted
- National Centre for Cell Science, Pune, India
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Lung cancer, particularly non-small cell lung cancer (NSCLC), remains the leading cause of cancer-related mortality worldwide, accounting for approximately 85% of lung cancer cases. Despite therapeutic advancements, the prognosis for advanced-stage NSCLC remains poor due to late diagnosis and high rates of therapeutic resistance. Recent studies have implicated the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway in NSCLC progression, revealing its dual role in innate immune activation and autophagy induction. Concurrently, cGAS-STING activation triggers non-canonical autophagy. We proposed a systems biology framework integrating mathematical model and network biology to elucidate how forkhead box class O (FOXOs) FOXO1 and FOXO3a serve as critical regulators linking cGAS-STING signaling with Interleukin-6 (IL-6) in promoting autophagy in NSCLC. Our integrative model highlights the complex interplay between immune signaling, metabolic reprogramming, and autophagic regulation in NSCLC. Further, sequence, phylogeny, structure, domain and protein-protein interaction studies identified crucial amino acids and their functions in regulating cGAS-STING-FOXO1 and cGAS-STING-FOXO3a interactions. These findings offer mechanistic insights into the dual role of FOXO proteins in autophagy mediated cancer progression and present potential components for the development of personalized therapeutic strategies aimed at targeting the cGAS-STING–FOXO–autophagy axis.
Keywords: FoxO1, FoxO3a, STING, Autophagy, mathematical model, network biology
Received: 20 Aug 2025; Accepted: 03 Nov 2025.
Copyright: © 2025 Rani, Khandibharad and Singh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Shailza Singh, shailza_iitd@yahoo.com
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