Astrocytic ALKBH5 contributes to depressive-like behaviors in mice through stress response. ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), is increased in patients with major depressive disorder (MDD) and depression models. Astrocytic ALKBH5 is more sensitive to stress than in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons or endothelial cells, produces antidepressant-like behaviors. Astrocytic ALKBH5 in the medial prefrontal cortex (mPFC) regulates depression-related behaviors bidirectionally. ALKBH5 modulates glutamate transporter-1 (GLT-1) m6A modification and increases GLT-1 expression in astrocytes. Astrocytic ALKBH5 knockout preserves stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy, and defective Ca²⁺ activity. Enhanced m6A modification with S-adenosylmethionine (SAMe) produces antidepressant-like effects. These findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors, and astrocytic ALKBH5 may be a therapeutic target for depression. MDD is a common psychiatric disorder with significant public health impact. Stress is a high-risk factor for depression, and epigenetic changes in brain cells under environmental stress impact functions to exacerbate depressive symptoms. The cellular specificity and sensitivity of stress effects on brain epitranscriptomics and their impact on depression remain unclear. m6A methylation regulates transcript processing and translation. Recent studies show that global m6A methylation in human and mouse whole blood is temporarily decreased following acute stress. RNA methyltransferases and demethylases are altered in MDD patients and depression models. Astrocytes are key components of the blood-brain barrier and wrap neuronal synapses to form tripartite synapses. Astrocytic dysfunction is linked to depression pathophysiology. Astrocytic epitranscriptome is more sensitive to environmental stressors and mediates depressive-like behaviors. ALKBH5 is increased in MDD patients and depression models. ALKBH5 in astrocytes is more sensitive to stress than in neurons and endothelial cells. Astrocytic ALKBH5 in the mPFC modulates glutamatergic transmission through m6A RNA methylation of GLT-1. Astrocytic ALKBH5 knockout maintains neuronal morphology and calcium activity under chronic stress. SAMe supplementation produces antidepressant-like behaviors. Astrocytic ALKBH5 regulates depression-related behaviors through m6A modification of GLT-1. SAMe induces antidepressant-like effects by altering global m6A modification. These findings suggest that astrocytic epigenetic changes bridge genetic and environmental factors in depression, indicating a potential therapy for depression by targeting m6A modifications in GLAstrocytic ALKBH5 contributes to depressive-like behaviors in mice through stress response. ALKBH5, an RNA demethylase of N6-methyladenosine (m6A), is increased in patients with major depressive disorder (MDD) and depression models. Astrocytic ALKBH5 is more sensitive to stress than in neurons and endothelial cells. Selective deletion of ALKBH5 in astrocytes, but not in neurons or endothelial cells, produces antidepressant-like behaviors. Astrocytic ALKBH5 in the medial prefrontal cortex (mPFC) regulates depression-related behaviors bidirectionally. ALKBH5 modulates glutamate transporter-1 (GLT-1) m6A modification and increases GLT-1 expression in astrocytes. Astrocytic ALKBH5 knockout preserves stress-induced disruption of glutamatergic synaptic transmission, neuronal atrophy, and defective Ca²⁺ activity. Enhanced m6A modification with S-adenosylmethionine (SAMe) produces antidepressant-like effects. These findings indicate that astrocytic epitranscriptomics contribute to depressive-like behaviors, and astrocytic ALKBH5 may be a therapeutic target for depression. MDD is a common psychiatric disorder with significant public health impact. Stress is a high-risk factor for depression, and epigenetic changes in brain cells under environmental stress impact functions to exacerbate depressive symptoms. The cellular specificity and sensitivity of stress effects on brain epitranscriptomics and their impact on depression remain unclear. m6A methylation regulates transcript processing and translation. Recent studies show that global m6A methylation in human and mouse whole blood is temporarily decreased following acute stress. RNA methyltransferases and demethylases are altered in MDD patients and depression models. Astrocytes are key components of the blood-brain barrier and wrap neuronal synapses to form tripartite synapses. Astrocytic dysfunction is linked to depression pathophysiology. Astrocytic epitranscriptome is more sensitive to environmental stressors and mediates depressive-like behaviors. ALKBH5 is increased in MDD patients and depression models. ALKBH5 in astrocytes is more sensitive to stress than in neurons and endothelial cells. Astrocytic ALKBH5 in the mPFC modulates glutamatergic transmission through m6A RNA methylation of GLT-1. Astrocytic ALKBH5 knockout maintains neuronal morphology and calcium activity under chronic stress. SAMe supplementation produces antidepressant-like behaviors. Astrocytic ALKBH5 regulates depression-related behaviors through m6A modification of GLT-1. SAMe induces antidepressant-like effects by altering global m6A modification. These findings suggest that astrocytic epigenetic changes bridge genetic and environmental factors in depression, indicating a potential therapy for depression by targeting m6A modifications in GL