Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder characterized by progressive cyst formation, tubular disruption, and eventual progression to end-stage renal disease. Although tolvaptan, a vasopressin V2 receptor antagonist, slows cyst growth, its limited efficacy and tolerability underscore the need for alternative therapeutic strategies (Torres et al., 2018). Emerging approaches target epithelial proliferation and fluid secretion through mechanisms involving mTOR, Src, RTKs, MAPKs, CFTR, TMEM16A, and heat shock proteins. While several interventions reduce cyst burden and total kidney volume (TKV) in preclinical models, translation to preservation of renal function in clinical studies remains limited. This body of work describes the identification of tumor-associated calcium signal transducer 2 (TACSTD2) as an early pathogenic biomarker in ADPKD and explores its potential as a therapeutic target (Smith et al., 2024). Transcriptomic analysis revealed Tacstd2 upregulation before cyst formation in polycystin-deficient mouse kidneys, human ADPKD biopsies, and iPSC-derived kidney organoids (Smith et al., 2024). Immunofluorescence localized TACSTD2 predominantly to cyst-lining epithelium with minimal expression in non-cystic tubules. Targeting TACSTD2 with Sacituzumab govitecan, an FDA-approved antibody-drug conjugate, in ADPKD kidney organoids selectively eliminated cyst-lining cells while preserving non-cystic structures, contrasting with the widespread cytotoxicity observed following free SN-38 administration. These findings propose that selective targeting of TACSTD2-overexpressing cyst epithelium represents a viable strategy to disrupt cyst expansion while minimizing injury to intact renal tissue. Further investigation into TACSTD2-directed therapies may broaden therapeutic approaches for managing ADPKD progression.