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Research Article: Mechanistic insights into lipoprotein(a)-induced cardiomyocyte ferroptosis via ROS/p38/p53 signaling

Date Published: 2026-07-13

Abstract:
Lipoprotein(a) [Lp(a)], a low-density lipoprotein-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. This study aimed to investigate the effects of Lp(a) on cardiomyocytes. A combination of in vitro cell culture and in vivo small animal models were used for investigations. Lp(a) induced ferroptosis through a redox-sensitive pathway via sequential p38 MAPK activation and p53-mediated transcriptional regulation. Exposure of AC16 human cardiomyocytes to Lp(a) triggered hallmark ferroptotic events, including intracellular Fe 2+ accumulation, an increase in malondialdehyde (MDA) levels, and concurrent increases in p38 MAPK (p-p38) phosphorylation. Pharmacological blockade of p38 using SB203580 or siRNA-mediated p38 silencing significantly attenuated these ferroptotic markers, confirming the central role of p38 in sensitizing cardiomyocytes to ferroptosis. p38 activation drove the nuclear translocation of p53, with both pharmacological p53 inhibition (pifithrin-?) and genetic p53 knockdown effectively mitigating Lp(a)-induced lipid peroxidation and cell death. Furthermore, Lp(a) promoted an increase in intracellular reactive oxygen species (ROS) levels and initiated p38 phosphorylation, subsequently activating p53 to suppress SLC7A11 expression. These cellular findings were validated in vivo using Lp(a)-treated C57BL/6J mice, which recapitulated cardiac dysfunction, as indicated by characteristic ferroptotic markers: myocardial Fe 2+ /MDA elevation, glutathione/cysteine depletion, and p38–p53 axis activation. Lp(a) activates p38 by increasing intracellular ROS levels and promotes ferroptosis in cardiomyocytes via SLC7A11 inhibition, which depends on p53 activation.

Introduction:
Cardiovascular diseases are a leading cause of mortality worldwide ( 1 ), with elevated lipid levels recognized as a known risk factor. However, even after lowering LDL cholesterol levels, many patients remain at a high risk of cardiovascular disease events. Lipoprotein(a) [Lp(a)] is a lipoprotein similar to low-density lipoprotein (LDL) cholesterol, with a core consisting of LDL-like particles surrounded by an outer layer of covalently bound apolipoprotein(a). Elevated Lp(a) levels have been identified as a…

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