Thrombin induces ferroptosis in triple-negative breast cancer through the cPLA2/ACSL4 signaling pathway

Ferroptosis is a recently identified form of regulated cell death that plays a crucial role in tumor suppression. In this study, we found that F2 (the gene encoding thrombin) was strongly upregulated in breast cancer (BRCA, TCGA Study Abbreviations) compared with normal samples and that lower F2 levels were associated with poorer prognosis in breast cancer patients. Thrombin induces ferroptosis in triple-negative breast cancer (TNBC) cells by activation of cytosolic phospholipase A2 alpha (cPLA2 alpha) activity to increase the release of arachidonic acid (AA). TNBC in all breast cancer subtypes exhibited the highest levels of PLA2G4A (the gene encoding cPLA2 alpha) and Acsl4, and inhibition of cPLA2 alpha and its downstream enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) reversed thrombin toxicity. In a mouse xenograft model of TNBC, thrombin treatment suppressed breast cancer growth which can be inhibited by ferroptosis inhibitor Liproxstatin-1 (Lip-1). Our study underscores the potential of the thrombin-ACSL4 axis as a promising therapeutic target for the treatment of TNBC.