USP32-mediated stabilization of MAPK12 promotes lung adenocarcinoma progression by inhibiting autophagy-ferroptosis.
TL;DR
Targeting the USP32-MAPK12 axis may restore cell death sensitivity in lung cancer, representing a promising LUAD therapeutic strategy.
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.