SGLT2 Inhibitor Repurposing Reveals Novel Treatment Avenues for Cystinosis

Background: Cystinosis is a prototype lysosomal storage disorder (LSD) triggered by inactivating mutations in cystinosin (CTNS), a proton-driven cystine transporter located on the surface of the lysosome. The deficiency of CTNS leads to cystine accumulation, mTORC1 hyperactivation, and impaired lysosome–autophagy degradation, with early proximal tubule (PT) dysfunction and systemic complications. Although mTORC1 inhibitors show promise in preclinical models, their lack of specificity and toxicity limits pediatric use. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed for diabetes, modulate nutrient sensing and mTORC1 activity in PT cells and slow chronic kidney disease progression. These effects mimic the benefits of fasting regimens, positioning SGLT2i as potential therapies for mTORC1-driven disorders like cystinosis. Methods: Using established mouse, rat, and zebrafish models, physiologically relevant PT cell cultures, organelle-based function assays, and multi-omics profiling, we evaluated the therapeutic efficacy of SGLT2i (e.g., dapagliflozin, empagliflozin) in restoring homeostasis and correcting PT dysfunction in cystinosis. Results: SGLT2 inhibition restored lysosomal degradation, suppressed aberrant growth, and promoted PT cell differentiation and reabsorptive function — thereby counteracting the defects induced by CTNS loss and cystine accumulation. Mechanistically, exposure to SGLT2i reduced mTORC1 activation by disrupting Ragulator–Rag GTPase-mediated lysosomal recruitment. In ctnsKO zebrafish expressing a PT/tubular proteinuria biosensor, SGLT2i normalized mTORC1 signalling, enhanced lysosomal catabolism, and reduced low-molecular-weight proteinuria (LMWP). In CtnsKO rats, early intervention with dapagliflozin at 10 weeks — before overt PT dysfunction but coinciding with elevated mTORC1 activity — prevented disease onset by suppressing mTORC1 hyperactivity, growth signalling and loss of PT differentiation. These functional rescues upon treatment with SGLT2i occurred in the absence of significant changes in cystine levels in treated CtnsKO rat kidneys. Conclusion: Taken together, these findings repurpose SGLT2 inhibition as a potential therapeutic avenue for treating dysregulated PT homeostasis in cystinosis.