Mechanistic Insights into Lipoprotein(a)-induced Cardiomyocyte Ferroptosis via ROS/p38/p53 Signalling

Background Lipoprotein(a) [Lp(a)], an LDL-like molecule covalently linked to apolipoprotein (a), is a residual cardiovascular risk factor with established atherogenic and antifibrinolytic properties. However, its direct involvement in cardiomyocyte injury mechanisms remains unclear. In this study, we investigated the effects of Lp(a) on cardiomyocytes. Methods The effects of Lp(a) on cardiomyocyte function were investigated using a combination of in vitro cell culture and in vivo small animal models. Results We identified a redox-sensitive pathway through which Lp(a) induces ferroptosis, an iron-dependent cell death mechanism driven by lipid peroxidation, via sequential p38 MAPK activation and p53-mediated transcriptional regulation. Exposure of AC16 human cardiomyocytes to Lp(a) was found to trigger hallmark ferroptotic events, including the accumulation of intracellular Fe²⁺ and an elevation in the levels of malondialdehyde (MDA), along with concurrent increases in the phosphorylation of p38 MAPK (p-p38). Pharmacological blockade of p38 using SB203580- or siRNA-mediated p38 silencing caused a significant attenuation of these ferroptotic markers, confirming the central role of p38 in sensitizing cardiomyocytes to ferroptosis. Mechanistic studies further established that p38 activation drives the nuclear translocation of p53, with both pharmacological p53 inhibition (pifithrin-α) and genetic p53 knockdown effectively mitigating Lp(a)-induced lipid peroxidation and cell death. Lp(a) was found to promote an elevation in the levels of intracellular reactive oxygen species (ROS) and initiates p38 phosphorylation, subsequently activating p53 to suppress the expression of SLC7A11, a key cystine/glutamate antiporter required for glutathione biosynthesis. These cellular findings were validated in vivo using Lp(a)-treated C57BL/6J mice, which recapitulated cardiac dysfunction, as indicated by characteristic ferroptotic markers, namely, myocardial Fe²⁺/MDA elevation, glutathione/cysteine depletion, and p38–p53 axis activation. Conclusion Our findings in this study revealed that Lp(a) activates p38 by increasing intracellular levels of ROS and promotes ferroptosis in cardiomyocytes via an inhibition of SLC7A11, which is dependent on the activation of p53.