Triple-negative breast cancer (TNBC) is a diverse subtype of breast cancer, constituting about 15–20% of all breast cancer cases. This study highlights KLHL29, an under-researched gene within the Kelch-like gene family, as an important tumor suppressor that influences chemoresistance in TNBC. Compared to adjacent normal tissues, KLHL29 expression was significantly reduced in breast cancer tissues, and lower levels of KLHL29 correlated with poor prognosis. Overexpression of KLHL29 inhibited, while its depletion promoted, the growth, migration, and invasion of TNBC cells. Mechanistically, KLHL29 interacted with the CUL3 E3 ligase, targeting the RNA-binding protein DDX3X for degradation via the proteasome. This degradation led to the destabilization of CCND1 mRNA, causing cell cycle arrest in the G0/G1 phase. Notably, combining the DDX3X inhibitor RK33 with platinum-based chemotherapy enhanced the suppression of TNBC, particularly in models with low KLHL29 and high DDX3X expression. These findings suggest that the KLHL29-DDX3X pathway plays a crucial role in TNBC progression and presents a promising strategy to overcome chemoresistance.
