Integrated transcriptomic analysis and experimental validation identify ACADL as a mitochondrial tumor suppressor via...

Mitochondrial dysfunction represents a recognized hallmark of cancer; however, the underlying molecular mechanisms contributing to this process in lung adenocarcinoma (LUAD) remain incompletely understood.

Differentially expressed genes (DEGs) in LUAD were identified by integrating datasets (GSE7670, GSE10072, and GSE32863), and were subsequently cross-referenced with mitochondria-related genes from the MitoCarta3.0 database. Hub genes were identified using the least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms. LUAD cell lines and xenograft models with stable overexpression of acyl-CoA dehydrogenase long chain (ACADL) were subsequently established. To assess the involvement of the FOXO3a/PUMA signaling axis in mediating tumor suppression, the selective FOXO3a inhibitor AS1842856 was employed.

Eight hub genes (ACADL, BIK, CAT, COX7A1, PAICS, PDK4, PRDX4, and PYCR1) demonstrated high diagnostic accuracy for LUAD, with area under the curve (AUC) values exceeding 0.80. ACADL, CAT, PDK4, and COX7A1 were significantly downregulated, whereas BIK, PAICS, PYCR1, and PRDX4 were upregulated in A549 and H1299 LUAD cell lines. Functional assays revealed that overexpression of ACADL suppressed cell proliferation, migration, and invasion, while inducing apoptosis in LUAD cells. Mechanistically, ACADL impaired mitochondrial bioenergetics by reducing intracellular ATP levels and promoting reactive oxygen species (ROS) accumulation. Additionally, ACADL enhanced mitochondrial fission by upregulating Drp1 and Fis1, and downregulating Mfn2 expression. Further mechanistic investigations indicated that ACADL activated the FOXO3a/PUMA signaling axis. In vivo, ACADL expression markedly inhibited tumor growth and disrupted mitochondrial homeostasis, an effect that was significantly attenuated upon administration of the FOXO3a inhibitor AS1842856.

ACADL functions as a mitochondria-associated tumor suppressor that impedes LUAD progression through activation of the FOXO3a/PUMA signaling pathway, underscoring its potential as a therapeutic target for LUAD.