HSPE1 promotes immune evasion in lung adenocarcinoma by mediating mitochondrial oxidative stress via histone lactylation-mediated SDHA transcriptional activation

Lung adenocarcinoma (LUAD) progression relies on the interplay between metabolic reprogramming and epigenetic modifications, yet the glycolysis-mediated histone lactylation is unexplored. This study aims to uncover the mechanism of this regulatory axis in LUAD progression. Bioinformatics analyses identified the enriched pathways of HSPE1 and SDHA. CIBERSORT and xCell algorithms investigated SDHA expression-immune infiltration correlations. qRT-PCR and immunohistochemical analysis revealed elevated histone lactylation in LUAD tissues. Furthermore, exogenous lactate treatment induced H3K18la and elevated SDHA in A549 cells. Chromatin immunoprecipitation assays confirmed the enrichment of H3K18la at the SDHA promoter region, directly regulating its transcriptional activity. Functional experiments demonstrated that SDHA overexpression enhanced cell viability and inhibited apoptosis by promoting oxidative stress (manifested by elevated malondialdehyde levels and altered superoxide dismutase and glutathione levels). Mechanistic investigations further revealed the enrichment of HSPE1 in the glycolysis pathway. HSPE1 overexpression enhanced glycolysis-derived lactate production, increasing H3K18la occupancy at the SDHA promoter, establishing a HSPE1-glycolysis-lactate-H3K18la-SDHA-oxidative stress positive feedback loop to accelerate LUAD progression. SDHA overexpression was negatively correlated with DC infiltration; excessive ROS induced DC cell death, indicating that HSPE1/SDHA axis-mediated oxidative stress may facilitate the immune escape of LUAD cells by impairing DC function. In vivo/in vitro functional assays verified the oncogenic function of this axis. In conclusion, HSPE1 drives the transcriptional activation of SDHA through the glycolysis-H3K18la epigenetic modification, thereby intensifying the oxidative stress microenvironment and promoting LUAD malignant progression. HSPE1-SDHA axis-induced oxidative stress may remodel tumor immune microenvironment via inhibiting DC antigen presentation, supporting combined immunotherapy development.