Neuronal Ceroid Lipofuscinoses (NCLs), collectively known as Batten disease (BD), are lysosomal storage disorders characterized by progressive vision loss, cognitive decline, and seizures. Given the difficulty of gene therapy in the CNS, there is interest in small-molecule therapeutics targeting disease-modifying pathways. We previously identified the glycosphingolipid Gb3 as a shared pathological marker in multiple BD forms1, but the mechanisms underlying its accumulation remain unclear. We conducted an siRNA-based high-content imaging screen using the Human Druggable Genome Library (~11,000 siRNAs) in ARPE-19 CLN3 knockout (KO) cells to identify regulators of Gb3 accumulation. The screening identified 115 genes whose silencing reduced Gb3 levels; 34 of these also lowered subunit c of mitochondrial ATP synthase (SCMAS). We focused on estrogen-related receptor alpha (ESRRA), a nuclear receptor implicated in autophagy. Both siRNA knockdown and pharmacological inhibition with XCT-790 reduced lysosomal Gb3 in CLN3KO and CLN7KO cells. ESRRA inhibition activated autophagic flux via the FOXO3a pathway (independently of TFEB) and increased autophagy markers. Transcriptomic analysis confirmed mitochondrial dysfunction in CLN3KO cells2, consistent with ESRRA role in mitochondrial regulation3. ESRRA depletion improved mitochondrial homeostasis. Finally, dietary XCT-790 treatment in CLN7KO mice reduced cortical and cerebellar Gb3 and SCMAS, decreased neuroinflammation, and improved motor performance. These findings identify ESRRA as a druggable target in BD, and XCT-790 as a promising therapy to restore lysosomal and mitochondrial function across multiple BD forms.