In oncology, permanent chemotherapy-induced alopecia (pCIA) remains an unfulfilled clinical need. Irreversible hair loss may result from permanent damage of hair follicle bulge epithelial stem cells (HFeSCs), some of which may undergo epithelial-mesenchymal transition (EMT). To prove our hypothesis, we treated ex vivo full-length HFs with 4HC, a cyclophosphamide metabolite 4HC, which routinely induces reversible CIA and sometimes pCIA. PPARγ signaling is known to have a protective role in eSCs biology. Therefore, we additionally tested whether NAC-GED-0507-Levo (NACGED), a PPARγ modulator, may protect HFs from 4HC-induced damage. Ex vivo, treatment with 4HC (3μM, 30μM) induced HF cytotoxicity and promoted dystrophic catagen development. Moreover, 4HC caused reduction of CK15+ bulge cells number, mainly by inducing apoptosis. Interestingly, 4HC also induced EMT in the bulge epithelium, as indicated by decreased E-cadherin expression, upregulation of fibronectin and appearance of vimentin+ intra-bulge cells. HFs pretreatment with 0.01-1mM NACGED before addition of 4HC provided relative protection from induction of cytotoxicity without preventing catagen development. Finally, NACGED treatment also antagonized CIA-induced intra-bulge EMT by counteracting both E-cadherin expression reduction and increased vimentin+ cells number. Our data suggest that pCIA irreversibility may indeed result from apoptosis and/or EMT-mediated destruction of CK15+bulge eSCs. Modulation of PPARγ signaling could provide an effective strategy for managing permanent hair loss in chemotherapy-treated cancer patients.