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

FIGURE 2.

Panel A shows Western blot bands for phosphorylated p38, total p38, and β-actin in AC16 cells at various times; panel B presents bright-field and fluorescence microscopy images of AC16 cells stained with Hoechst and p-p38, including control and Lp(a) conditions. Panel C displays Western blots for p-p38, p38, GPX4, ACSL4, and β-actin in AC16 cells with or without SB203580 and Lp(a) treatments. Panels D, E, and F present bar graphs quantifying cell death ratio, fluorescence intensity, and MDA levels, respectively, for the same conditions. Panel G shows Western blot bands for p-p38, p38, GPX4, ACSL4, and β-actin in AC16 cells treated with scrambled or p38 siRNA and Lp(a). Panels H, I, and J include bar graphs depicting cell death ratio, fluorescence intensity, and MDA level for the conditions in panel G.

p38 sensitises cardiomyocytes to Lp(a)-induced ferroptosis. (A) Time-dependent upregulation of phosphorylated p38 (p-p38) protein levels was observed in AC16 cells treated with 2 μmol/L Lp(a) for 0, 3, 6, 12, and 24 h. (B) Confocal microscopy revealed increased p-p38 expression in both the cytoplasm and nuclei of AC16 cells following 24-h exposure to 2 μmol/L Lp(a). (C) Pre-treatment with 10 μmol/L SB203580 for 1 h attenuated the Lp(a)-induced upregulation of p-p38 and ACSL4 expression, as well as the downregulation of GPX4 expression. (D) SB203580 pre-treatment for 1 h suppressed Lp(a)-triggered cell death. (E) SB203580 pre-treatment for 1 h reduced Lp(a)-induced elevation of FerroOrange fluorescence intensity. (F) SB203580 pre-treatment for 1 h mitigated Lp(a)-induced increases in intracellular MDA levels. (G) p38 knockdown via siRNA inhibited Lp(a)-mediated upregulation of p-p38 and ACSL4 expression, as well as the downregulation of GPX4 expression. (H) p38 knockdown via siRNA prevented Lp(a)-induced cell death. (I) p38 knockdown via siRNA attenuated Lp(a)-induced enhancement of FerroOrange fluorescence intensity. (J) p38 knockdown via siRNA attenuated Lp(a)-induced increases in intracellular MDA levels. *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).