Safety Lessons for YAP/TAZ-TEAD Inhibition: From Mechanism to Translation.

The human Hippo pathway restricts tissue growth primarily through mammalian Ste20-like kinase 1/2 (MST1/2) and large tumor suppressor 1/2 (LATS1/2)-mediated regulation of transcriptional activators Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). When this brake is lifted, nuclear YAP/TAZ cooperate with transcriptional enhanced associate domain transcription factors 1-4 (TEAD1-4) to drive context-specific transcriptional programs that support proliferation, survival, and repair. Therapeutic strategies targeting TEADs using lipid pocket binders, interface 3 (Ω-loop) protein-protein interaction inhibitors, and degraders have opened promising avenues to inhibit this signaling pathway in cancers. Alongside reported clinical antitumor efficacy in mesothelioma and neurofibromatosis type 2 (NF-2)-deficient tumors (see Garralda et al., Ann Oncol 36: S562 [2025]; Yap et al. Nat Med 31: 4281-4290 [2025]; and Yap et al. Cancer Res 83: CT006 [2023]), kidney-related adverse effects have recently emerged, characterized nonclinically or clinically by proteinuria, albuminuria, podocyte injury, and tubular degeneration. Evidence from genetics, organoids, and human-induced pluripotent stem cell (hiPSC) models indicates that YAP/TAZ-TEAD activity is integral to podocyte and tubular homeostasis, providing a mechanistic explanation for the kidney susceptibility. In this review, we summarize nonclinical and early clinical safety observations with pan-TEAD inhibitors, highlight organs most at risk, and discuss approaches that could be taken to optimize the therapeutic index of TEAD inhibitors, like paralog selectivity, adaptive/intermittent dosing, and monitoring of translational biomarkers with pharmacodynamic readouts. Integrating the mechanistic insights and safety lessons learned so far from targeting this pathway could guide safer clinical development of TEAD-directed therapies in the future.