Curcumin-Induced Vacuolizing Stress Reveals a Vulnerability Associated with NF1 Loss in Schwann Cells

Neurofibromatosis type 1 (NF1) predisposes to peripheral nerve sheath tumors arising from Schwann-lineage cells with biallelic NF1 loss and remains in need of biologically informed strategies compatible with chronic disease management. Curcumin has attracted interest in NF1, but its effects in disease-relevant cells remain unclear. Here, we investigated curcumin responses in patient-derived NF1-deficient Schwann cells. Curcumin induced the progressive accumulation of cytoplasmic vacuoles resembling those elicited by a reference methuosis inducer, without prominent evidence of canonical apoptotic features. Vacuolization was associated with impaired long-term clonogenic recovery, indicating a durable loss of proliferative fitness. NF1-deficient Schwann cells displayed lower levels of NRF2, thioredoxin, and SOD1 than NF1-proficient cells under basal and curcumin-treated conditions, defining a distinct NF1-associated antioxidant-response context. Consistent with a functionally relevant redox-sensitive component, N-acetylcysteine pretreatment reduced curcumin-induced vacuolization to near-basal levels and substantially improved clonogenic recovery after drug washout. NF1-proficient Schwann cells showed an attenuated vacuolizing response, whereas acute NF1 silencing in hTERT RPE-1 cells enhanced curcumin-induced vacuolization in an independent cellular background. Together, these findings identify an NAC-sensitive vacuolizing response associated with loss of cellular fitness as a previously underappreciated vulnerability of NF1-deficient cells and provide a disease-relevant framework for understanding curcumin responsiveness in NF1.