Lithium induces autophagy by inhibiting inositol monophosphatase (IMPase). This study demonstrates that lithium enhances the clearance of autophagy substrates, such as mutant huntingtin and α-synuclein, through a mTOR-independent pathway. Lithium inhibits IMPase, leading to reduced free inositol and myo-inositol-1,4,5-triphosphate (IP3) levels. This decrease in IP3 levels is downstream of the autophagy effect, as it is abrogated by treatments that increase IP3. The autophagy-inducing effect of lithium is independent of mTOR and may be beneficial for treating neurodegenerative diseases like Huntington's disease (HD), where the toxic protein is an autophagy substrate. The study shows that lithium facilitates the clearance of mutant huntingtin and α-synuclein by inducing autophagy. This effect is not mediated by glycogen synthase kinase 3β (GSK-3β) but is due to IMPase inhibition. Lithium treatment significantly enhances the clearance of these proteins, and this effect is blocked by the autophagy inhibitor 3-methyladenine (3-MA). Additionally, lithium-induced autophagy is confirmed by increased LC3-II levels and the formation of autophagic vesicles. Lithium also enhances the clearance of mutant α-synuclein, which is a key protein in Parkinson's disease. The effect of lithium on autophagy is independent of mTOR, as shown by the lack of effect on mTOR phosphorylation. The study further shows that lithium and an IMPase inhibitor (L-690,330) both induce autophagy and enhance the clearance of mutant proteins. This effect is mediated by the reduction of free inositol and IP3 levels, which are critical for autophagy regulation. The study also demonstrates that lithium and other mood-stabilizing drugs, such as carbamazepine (CBZ) and valproic acid (VPA), can deplete intracellular inositol, which may contribute to their therapeutic effects in neurodegenerative diseases. The findings suggest that targeting autophagy through IMPase inhibition could be a novel therapeutic strategy for neurodegenerative disorders.Lithium induces autophagy by inhibiting inositol monophosphatase (IMPase). This study demonstrates that lithium enhances the clearance of autophagy substrates, such as mutant huntingtin and α-synuclein, through a mTOR-independent pathway. Lithium inhibits IMPase, leading to reduced free inositol and myo-inositol-1,4,5-triphosphate (IP3) levels. This decrease in IP3 levels is downstream of the autophagy effect, as it is abrogated by treatments that increase IP3. The autophagy-inducing effect of lithium is independent of mTOR and may be beneficial for treating neurodegenerative diseases like Huntington's disease (HD), where the toxic protein is an autophagy substrate. The study shows that lithium facilitates the clearance of mutant huntingtin and α-synuclein by inducing autophagy. This effect is not mediated by glycogen synthase kinase 3β (GSK-3β) but is due to IMPase inhibition. Lithium treatment significantly enhances the clearance of these proteins, and this effect is blocked by the autophagy inhibitor 3-methyladenine (3-MA). Additionally, lithium-induced autophagy is confirmed by increased LC3-II levels and the formation of autophagic vesicles. Lithium also enhances the clearance of mutant α-synuclein, which is a key protein in Parkinson's disease. The effect of lithium on autophagy is independent of mTOR, as shown by the lack of effect on mTOR phosphorylation. The study further shows that lithium and an IMPase inhibitor (L-690,330) both induce autophagy and enhance the clearance of mutant proteins. This effect is mediated by the reduction of free inositol and IP3 levels, which are critical for autophagy regulation. The study also demonstrates that lithium and other mood-stabilizing drugs, such as carbamazepine (CBZ) and valproic acid (VPA), can deplete intracellular inositol, which may contribute to their therapeutic effects in neurodegenerative diseases. The findings suggest that targeting autophagy through IMPase inhibition could be a novel therapeutic strategy for neurodegenerative disorders.