VGF-Mediated Mitochondrial Remodeling Fuels Lung Adenocarcinoma Brain Metastasis

Lung adenocarcinoma cells exhibit a marked propensity for brain metastasis, in which they face unique metabolic challenges imposed by the microenvironment. The mechanisms that enable lung adenocarcinoma cells to adapt to these constraints represent potential therapeutic targets. In this study, we identified the neuropeptide VGF as a clinically relevant driver of brain metastatic progression. VGF expression was markedly upregulated in lung adenocarcinoma brain metastases, and elevated VGF expression was associated with an increased risk of brain metastasis and poor survival outcomes. Moreover, brain-derived signals induced VGF expression in lung adenocarcinoma cells, promoting cell survival and proliferation through enhanced mitochondrial oxidative phosphorylation and ATP production. Mechanistically, the N-terminal domain of VGF-a nonclassically secreted peptide-interacted with the hydrolase domain of ABHD12B to suppress cardiolipin degradation, leading to increased cardiolipin levels, stabilization of mitochondrial membranes, and a shift toward mitochondrial fusion over excessive fission. These changes helped meet the heightened energetic demands of metastatic cells in the brain. Genetic deletion of the VGF N-terminal domain disrupted mitochondrial fusion, impaired oxidative metabolism, and significantly reduced brain colonization in mouse models of brain metastasis. Together, these findings uncover a role for VGF and establish the VGF-ABHD12B-cardiolipin axis as a critical mechanism underlying metabolic adaptation in lung adenocarcinoma brain metastases, highlighting the potential of this pathway as a therapeutic target for intervention. SIGNIFICANCE: The N-terminal domain of VGF is required for sustaining mitochondrial fusion and oxidative phosphorylation to support metabolic adaptation in lung cancer brain metastases, underscoring a potentially targetable mechanism to impair brain colonization.