Abstract Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer, marked by rapid progression, high recurrence, and limited treatment options. Emerging evidence suggests that both oxidative stress signaling and the tumor immune microenvironment (TIME) contribute to therapy resistance in TNBC. Kaempferol, a naturally occurring flavonoid found in fruits and vegetables, has shown promise as a multi-target anticancer compound, but its mechanisms of action remain incompletely understood. In this study, we explored how kaempferol regulates tumor growth, immune checkpoint activity, and inflammatory mediators in two genetically distinct TNBC cell lines, MDA-MB-231 (Caucasian) and MDA-MB-468 (African American). The results showed that kaempferol significantly reduced cell viability and proliferation, induced apoptosis, and caused S-phase cell cycle arrest by inhibiting the expression of CDK1, CDK4, CDK6, and CDK7. Under cytokine stimulation, kaempferol downregulated IFN-γ-induced PD-L1 via inhibition of the JAK1/STAT3 pathway and reduced TNF-α-induced CCL2 expression, indicating broad immunomodulatory activity. To understand the contribution of redox regulation, we silenced the transcription factor Nrf2 (NFE2L2) using Nrf2 siRNA. Interestingly, Nrf2 knockdown did not alter kaempferol’s inhibition of PD-L1, suggesting that PD-L1 modulation occurs independently of Nrf2. In contrast, silencing Nrf2 markedly increased CCL2 and transglutaminase-2 (TGM2) expression, confirming Nrf2’s repressive role in inflammatory signaling. Kaempferol treatment reversed these increases, bringing CCL2 and TGM2 levels back towards baseline. Together, these findings highlight kaempferol’s dual ability to regulate both immune checkpoints and inflammatory mediators through distinct, Nrf2-dependent and independent pathways. In conclusion, this study describes the anticancer effects of kaempferol through various molecular mechanisms and targets, which may lead to the development of more effective adjuvant therapies against TNBC. Citation Format: Sukhmandeep Kaur, Patricia Mendonca, Shubham D. Mishra, Karam F. A. Soliman. Nrf2 role in regulating kaempferol’s inhibitory action on CDKs, PD-L-1, CCL2, and TGM2 in triple-negative breast cancer cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 396.
Kaur et al. (Fri,) studied this question.