Paclitaxel is an effective chemotherapy drug for breast cancer (BC); however, drug resistance affects long-term clinical applications. In this study, we aimed to explore whether a natural compound, tetrahydrocurcumin (THC), could sensitize BC to albumin-bound paclitaxel (ab-PTX). The in vitro sensitization effect of THC to ab-PTX was evaluated in human BC cell lines, and in vivo chemosensitivity was measured using a xenograft BC tumor model. The expression of secreted protein acidic and rich in cysteine (SPARC), a speculated protein interacting with ab-PTX, was measured. Methylation-specific polymerase chain reaction (MSP) was used to further explore whether demethylation of SPARC by THC contributed to its chemosensitivity capabilities. Higher SPARC expression was correlated with a better prognosis in patients with BC. In vitro analysis showed THC enhanced the inhibitory effect of ab-PTX on BC cells and xenograft tumors and showed significant chemosensitivity. This enhancement mainly relied on upregulating the expression of SPARC through downregulating methylation of the SPARC gene. The demethylating agent, 5-Aza-2'-deoxycytidine (5-Aza-Cdr), decreased THC's chemosensitivity effect, further confirming this molecular mechanism. THC enhanced the inhibitory effect of ab-PTX in BC by downregulating methylation of the SPARC gene. Further, upregulated SPARC increased the efficacy of ab-PTX.Copyright © 2022 Dongjie Qiu et al.