Z-FY-CHO (Z-Phe-Tyr-CHO) is a specific and potent cathepsin L (CTSL) inhibitor [1] [2].

Pretreatment with Z-FY-CHO (10 μM, for 1 h) effectively mitigated cell death caused by 6-OHDA in SH-SY5Y cells, demonstrating its protective role. It also prevented the 6-OHDA-induced surge in CTSL protein levels and modulated autophagy markers by increasing LC3-II and decreasing P62 expression, thereby suggesting enhanced autophagic activity. Additionally, Z-FY-CHO impeded the activation of apoptosis markers caspase-3 and PARP. In U251 cells, employing Z-FY-CHO (10 μM) or cathepsin L shRNA transfection notably heightened radiosensitivity. This effect was paralleled by elevated irradiation-induced DNA damage, G2/M phase arrest, and apoptosis, evidenced by increased Bax and reduced Bcl-2 levels, underscoring the critical role of cathepsin L inhibition or knockdown in these processes [1][2].

Administering Z-FY-CHO intraperitoneally at doses ranging from 2.5 to 10 mg/kg for four weeks dose-dependently mitigates bone weight loss in the ovariectomized mouse, a model for osteoporosis research. The mechanism through which Z-FY-CHO exerts its effects involves the suppression of bone resorption by inhibiting collagen degradation [3].