Disruption of the autophagy-ferroptosis axis by ubiquitin-specific peptidase 20-mediated Sequestosome 1 stabilization drives lung adenocarcinoma progression

  • Int J Biol Macromol. 2026 Jun 23:153185. doi: 10.1016/j.ijbiomac.2026.153185.
Dan Cui  1 ,  Yifan He  2 ,  Zhengwei Yu  2 ,  Haoyu Xie  2 ,  Bin Mo  2 ,  Pei Xu  2 ,  Rui Hu  2 ,  Lianyong Jiang  2 ,  Yueyan Lou  3 ,  Haibo Xiao  4
Affiliations
  • 1. Mini-invasive Interventional Therapy Centre, Shanghai East Hospital, School of Medicine, Tongji University, No.150 Jimo Road, Pudong New Area, Shanghai, 200120, China.
  • 2. Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China.
  • 3. Department of Respiratory Medicine, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, No.160 Pujian Road, Pudong New Area, Shanghai, 200127, China. Electronic address: [email protected].
  • 4. Department of Cardiothoracic Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.1665 Kongjiang Road, Yangpu District, Shanghai, 200092, China. Electronic address: [email protected].
PMID: 42336010 DOI: 10.1016/j.ijbiomac.2026.153185
Abstract

Objective: To investigate the role of the deubiquitinating enzyme USP20 in lung adenocarcinoma (LUAD) and determine how it regulates Autophagy and Ferroptosis during tumor progression.

Methods: Integrative analyses of single-cell transcriptomic data and LASSO regression identified USP20 as a candidate oncogenic regulator in LUAD. Gain- and loss-of-function approaches were used to examine its role in Autophagy and Ferroptosis. Protein interactions and ubiquitination regulation were analyzed by co-immunoprecipitation, cycloheximide chase, and ubiquitination assays. Functional assays and xenograft models were performed to evaluate the biological and therapeutic significance of USP20 inhibition.

Results: USP20 was markedly upregulated in LUAD and negatively associated with Autophagy and Ferroptosis signatures. USP20 depletion suppressed tumor cell proliferation and migration, enhanced autophagic flux, and increased Ferroptosis sensitivity, whereas USP20 overexpression produced the opposite effects. Mechanistically, USP20 interacted with SQSTM1/p62 and removed its K48-linked ubiquitin chains, thereby stabilizing p62 and blocking autophagic flux. Stabilized p62 further maintained the SQSTM1-NCOA4 complex, limiting ferritinophagy and consequently suppressing Ferroptosis. Pharmacological inhibition of USP20 restored Ferroptosis signaling and significantly suppressed LUAD progression in vitro and in vivo.

Conclusion: These findings identify the USP20-SQSTM1-autophagy axis as a key mechanism mediating Ferroptosis resistance in LUAD and underscore USP20 as a promising therapeutic target.

Keywords
Deubiquitination; Ferroptosis; Lung adenocarcinoma; SQSTM1; USP20.
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