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. 2026 Jul 13;13:1858249. doi: 10.3389/fmed.2026.1858249

FIGURE 3.

Panel A displays western blot results showing expression levels of P53, SLC7A11, and β-Actin proteins in AC16 cells at time points from zero to twenty-four hours. Panel B contains four columns of images for control and Lp(a)-treated AC16 cells: bright-field, Hoechst-stained nuclei (blue), P53 immunofluorescence (green), and merged images. Panel C shows a bar graph of relative cysteine levels over time, while Panel D demonstrates relative GSH levels over time, both compared to control. Panel E presents immunoprecipitation and western blot analyses of p-p38 and P53 with time points at zero, twelve, and twenty-four hours, as well as IgG control. Panel F shows western blots for P53, SLC7A11, GPX4, ACSL4, and β-Actin under Lp(a) and SB203580 inhibitor treatments. Panels G and H display bar graphs of cysteine and GSH levels, respectively, in the presence or absence of SB203580 and Lp(a). Panel I shows western blots for phosphorylated p38, total p38, P53, SLC7A11, GPX4, ACSL4, and β-Actin in samples treated with scrambled or p38 siRNA and Lp(a). Panels J and K provide bar graphs comparing cysteine and GSH levels for these treatments, indicating statistical significance.

Lp(a) activates p53 through p38-mediated signaling. (A) Time-dependent upregulation of p53 protein expression and concurrent downregulation of SLC7A11 were observed in AC16 cells treated with 2 μmoL/L Lp(a) for 0, 3, 6, 12, and 24 h. (B) Confocal microscopy demonstrated increased p53 accumulation in both the cytoplasm and nuclei of AC16 cells following 24-h exposure to 2 μmoL/L Lp(a). (C) Intracellular cysteine levels exhibited a time-dependent decrease in AC16 cells treated with 2 μmoL/L Lp(a) across 0–24 h. (D) Intracellular glutathione levels showed a time-dependent reduction in AC16 cells treated with 2 μmol/L Lp(a) across 0–24 h. (E) Co-immunoprecipitation (Co-IP) combined with western blotting revealed that p-p38 co-precipitation with p53 increased progressively with prolonged Lp(a) exposure. (F) Pre-treatment with 10 μmoL/L SB203580 for 1 h attenuated Lp(a)-induced upregulation of p53 and ACSL4 as well as downregulation of SLC7A11 and GPX4. (G) SB203580 pre-treatment for 1 h mitigated Lp(a)-mediated cysteine depletion. (H) SB203580 pre-treatment for 1 h suppressed Lp(a)-induced glutathione reduction. (I) p38 knockdown via siRNA abolished Lp(a)-triggered p-p38 activation, upregulation of p53 and ACSL4 as well as downregulation of SLC7A11 and GPX4. (J) p38 knockdown via siRNA prevented Lp(a)-induced cysteine depletion. (K) p38 knockdown via siRNA inhibited Lp(a)-mediated GSH reduction. *P <0.01 versus the control group; #P <0.01 versus the Lp(a) group. The values are expressed as mean ± SD (n = 6 per group).