USP32-mediated stabilization of MAPK12 promotes lung adenocarcinoma progression by inhibiting autophagy-ferroptosis.

Authors

Qiang Zhang, Hongxu Sheng, Dongnan Ping, Jixiang Gao

Published in

Communications biology. Jul 19, 2026. Epub Jul 19, 2026.

Abstract

Lung adenocarcinoma (LUAD), the most common non-small cell lung cancer, often resists ferroptosis and autophagy-two tumor-suppressive, therapy-sensitive regulated cell death pathways. MAPK12 (a stress-responsive p38 MAPK kinase) boosts LUAD cell survival under oxidative stress, while USP32 (a LUAD-upregulated deubiquitinase) correlates with poor prognosis. However, the USP32-MAPK12 axis's regulatory role in LUAD ferroptosis and autophagy remains uninvestigated. USP32/MAPK12 expression in LUAD tissues/cell lines was detected via Western blotting and immunohistochemistry. Functional assays (colony formation, Transwell migration, ferroptosis/mitophagy tests) were performed after gene overexpression/knockdown. Protein interactions and ubiquitination were analyzed by co-immunoprecipitation, with in vivo validation using xenograft models. USP32 overexpression in LUAD correlated with reduced overall survival; it stabilized MAPK12 by removing K48-linked ubiquitin chains to block proteasomal degradation. USP32/MAPK12 knockdown activated autophagy/ferroptosis (elevated LC3B/ACSL4/Fe²⁺/MDA, reduced GPX4/p62), inhibited LUAD cell proliferation/migration in vitro and tumor growth in vivo. Thus, targeting the USP32-MAPK12 axis may restore cell death sensitivity, representing a promising LUAD therapeutic strategy.

PMID:
42477452
Bibliographic data and abstract were imported from PubMed on 21 Jul 2026.

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