Neuronal differentiation regulator CEND1 coordinately suppresses tumor growth and energetics via AMPK signaling in brain glioma

The aggressive proliferation and metabolic adaptability of glioma contribute to poor clinical prognosis, necessitating novel targets concurrently reprogram glioma cells toward a neuron-like, less proliferative, and metabolically suppressed state. Here, we identified neuronal differentiation factor CEND1 as a candidate and explored its impact on glioma growth and metabolism. We demonstrated that CEND1 was significantly reduced in high-grade gliomas and inversely correlated with patient survival. Elevated CEND1 in glioma cells induced a neuron-like morphology, accompanied with attenuated proliferation and migration. CEND1 overexpression suppressed tumor growth and prolonged the survival of animal models of intracranial orthotopic tumor formation. Metabolomics and biochemical assays revealed that CEND1 inhibited PDH activity and mitochondrial oxidative phosphorylation, ultimately reducing ATP levels. Mechanistically, CEND1 activated AMPK to induce cell proliferation arrest and enhance metformin sensitivity. Altogether, our findings reveal that CEND1 coordinates neuronal differentiation with mitochondrial energetic metabolic suppression to exert anti-proliferative function in glioma, supporting its role as a potential target for glioma therapy.