Mechanisms
Lp(a) drives cardiomyocyte ferroptosis through a ROS-p38-p53-SLC7A11 pathway, in vitro and mouse study finds (Front Med (Lausanne) 2026)
Original title: Mechanistic insights into lipoprotein(a)-induced cardiomyocyte ferroptosis via ROS/p38/p53 signaling
This mechanistic study combined human AC16 cardiomyocyte culture with a C57BL/6J mouse model to test whether lipoprotein(a) injures heart muscle cells directly. Lp(a) exposure raised intracellular reactive oxygen species, triggering p38 MAPK phosphorylation that drove nuclear translocation of p53 and suppression of SLC7A11, producing the hallmark ferroptotic signature of intracellular Fe2+ accumulation, elevated malondialdehyde, and glutathione and cysteine depletion. Pharmacological or siRNA blockade of p38, and pharmacological or genetic inhibition of p53, each attenuated ferroptotic markers and lipid peroxidation, and the pathway was reproduced in Lp(a)-treated mice with cardiac dysfunction. This is preclinical mechanistic evidence for a ROS/p38/p53/SLC7A11 ferroptosis axis as a route from elevated Lp(a) to cardiomyocyte injury, not yet tested in humans.
Original abstract
Objective: 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.
Methods: A combination of in vitro cell culture and in vivo small animal models were used for investigations.
Results: 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 Fe2+ 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-α) 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 Fe2+/MDA elevation, glutathione/cysteine depletion, and p38-p53 axis activation.
Conclusion: Lp(a) activates p38 by increasing intracellular ROS levels and promotes ferroptosis in cardiomyocytes via SLC7A11 inhibition, which depends on p53 activation.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.