Lithium induces autophagy by inhibiting inositol monophosphatase (IMPase), leading to free inositol depletion and decreased levels of myo-inositol-1,4,5-triphosphate (IP3). This effect enhances the clearance of autophagy substrates, such as mutant huntingtin and α-synuclein, without involving glycogen synthase kinase-3β inhibition. The autophagy-inducing effect of lithium is independent of mTOR and may provide a novel pharmacological strategy for treating neurodegenerative diseases like Huntington's disease.Lithium induces autophagy by inhibiting inositol monophosphatase (IMPase), leading to free inositol depletion and decreased levels of myo-inositol-1,4,5-triphosphate (IP3). This effect enhances the clearance of autophagy substrates, such as mutant huntingtin and α-synuclein, without involving glycogen synthase kinase-3β inhibition. The autophagy-inducing effect of lithium is independent of mTOR and may provide a novel pharmacological strategy for treating neurodegenerative diseases like Huntington's disease.