Inhibition of recurrence and metastasis in triple-negative breast cancer through nanoparticle-mediated silencing of LPCAT1 to remodel ATP energy metabolism.

Breast cancer remains the most prevalent malignancy among women worldwide, with triple-negative breast cancer (TNBC) representing its most aggressive and lethal subtype. TNBC is characterized by high rates of recurrence and lung metastasis after surgery, severely impacting patient quality of life. Recent studies highlight the critical role of metabolic reprogramming in driving cancer recurrence, migration, and invasion. While the underlying mechanisms remain complex and not fully elucidated, transcriptomic analyses comparing primary and metastatic breast cancer tissues from TNBC and Luminal patients have identified lysophosphatidylcholine acyltransferase 1 (LPCAT1) as a key enzyme upregulated in lung metastases and TNBC. LPCAT1 is strongly associated with poor prognosis due to its activation of the TGFβ signaling pathway. This activation is driven by LPCAT1's ability to increase cellular ATP levels, fostering a high-energy state that stimulates ATPase activity. Consequently, ATP-dependent chromatin remodeling via the BAF complex, which includes double PHD finger 2 (DPF2) as a critical subunit, regulates gene transcription essential for tumor progression. Through the LPCAT1-DPF2-TGFBR2 axis, TNBC cells enhance TGFβ signaling, promoting malignant behavior and metastasis. Addressing this, we developed a reduction-responsive nanoparticle platform for the systemic delivery of LPCAT1-targeted siRNA (siLPCAT1), which has shown significant efficacy in suppressing TNBC tumor growth and metastasis. These findings suggest that nanoparticle-mediated siLPCAT1 delivery represents a promising therapeutic strategy for advanced TNBC treatment.