The Autophagy-Oxidative Stress Circuit: A Conductor of Cell Fate

Yi Lu^1,#, Lixiang Wang^1,#, Jiaheng Xu^1,#, Heru Wang¹, Jiayu Li¹, Wanshun Li¹, Xinyi Su¹, Hongyu Li², Deyu Zhang^1,*, Zhendong Jin^1,*, Haojie Huang^1,*
1 Department of Gastroenterology, The First Affiliated Hospital of Naval Medical University, 168 Changhai Road, Shanghai, China
2 Department of Gastroenterology, Changxing County People’s Hospital, Changxing County, Huzhou City, China
* Corresponding Author: Deyu Zhang. Email: email ; Zhendong Jin. Email: email ; Haojie Huang. Email: email
# These authors contributed equally to this work and should be considered co-first authors

BIOCELL https://doi.org/10.32604/biocell.2026.082978

Received 26 March 2026; Accepted 29 May 2026; Published online 12 June 2026

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Abstract

Autophagy and oxidative stress form a bidirectional and dynamic regulatory network governing cell fate. Dysregulation of this crosstalk contributes to the pathogenesis of various diseases, including cancer, neurodegeneration, inflammation, metabolic disorders, and aging. Therefore, a deep understanding of the molecular mechanisms underlying the interplay between autophagy and oxidative stress provides a theoretical foundation for developing therapeutic strategies targeting this axis. This review synthesizes recent literature on the underlying molecular mechanisms. Oxidative stress drives autophagic initiation through multiple interconnected pathways, including direct oxidative modification of core autophagy-related proteins, modulation of canonical signaling cascades, activation of nuclear transcription factors, and induction of selective autophagy. In turn, autophagy acts as a pivotal cytoprotective mechanism by eliminating reactive oxygen species (ROS) generated by damaged organelles, sustaining metabolic homeostasis, and reinforcing antioxidant signaling, thereby counteracting oxidative damage. The balance between these two processes determines whether cells adapt and survive, undergo programmed cell death, or enter senescence.