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Objective <p>This study aimed to elucidate the mechanism of Lactate Dehydrogenase A (LDHA) in senescent fibroblast-derived exosomes during skin photoaging, focusing on the molecular pathway by which it regulates Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) expression through histone lactylation, thereby inducing ferroptosis and accelerating skin photoaging.</p> Methods <p>An ultraviolet B (UVB)-induced senescence model was established using human foreskin fibroblasts. Exosomes were isolated from senescent fibroblasts and characterized. Their features and uptake were assessed using Western blot, transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and immunofluorescence. Small interfering RNA was employed to knock down LDHA and ACSL4 gene. Pharmacological inhibitors (FX11, Ferrostatin-1) and sodium lactate rescue experiments were utilized. Lactate levels, histone H3K18 lactylation modification, ACSL4 transcriptional activity, and ferroptosis markers were detected to assess the effects of ACSL4 gene lactylation on ferroptosis. The biological effects of exosomal LDHA in photoaged tissue were validated using an in vivo UVB-irradiated mouse model.</p> Results <p>UVB irradiation induced fibroblast senescence and significantly upregulated LDHA expression. Exosomes from senescent fibroblasts were effectively taken up by HaCaT cells, leading to increased lactate levels and enhanced histone H3K18 lactylation in recipient cells. LDHA knockdown or inhibition downregulated ACSL4 expression and suppressed ferroptosis, whereas exogenous lactate partially restored these effects. RNA sequencing and ChIP-qPCR results indicated that LDHA-mediated lactylation modification was enriched at the ACSL4 promoter region, enhancing its transcriptional activity. In vivo experiments further confirmed that senescent exosomes accelerated UVB-induced skin collagen degradation and ferroptosis, while LDHA intervention significantly alleviated photoaging damage.</p> Conclusion <p>Senescent fibroblast-derived exosomes deliver LDHA, promoting histone lactylation modification, which upregulates ACSL4 expression and activates the ferroptosis pathway, ultimately accelerating skin photoaging. This study reveals the coupling mechanism between metabolic signaling and epigenetic regulation in skin aging, providing new molecular targets and a theoretical basis for anti-photoaging therapy.</p>

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Role of LDHA in senescent fibroblast exosomes promoting ferroptosis via histone lactylation-mediated ACSL4 regulation in skin photoaging

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月14日

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  • Tingting Yan,
  • Lixia Huang,
  • Jingjing Tao,
  • Yunling Yan,
  • Yiping Zhong,
  • Xuebiao Peng

摘要

Objective

This study aimed to elucidate the mechanism of Lactate Dehydrogenase A (LDHA) in senescent fibroblast-derived exosomes during skin photoaging, focusing on the molecular pathway by which it regulates Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) expression through histone lactylation, thereby inducing ferroptosis and accelerating skin photoaging.

Methods

An ultraviolet B (UVB)-induced senescence model was established using human foreskin fibroblasts. Exosomes were isolated from senescent fibroblasts and characterized. Their features and uptake were assessed using Western blot, transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and immunofluorescence. Small interfering RNA was employed to knock down LDHA and ACSL4 gene. Pharmacological inhibitors (FX11, Ferrostatin-1) and sodium lactate rescue experiments were utilized. Lactate levels, histone H3K18 lactylation modification, ACSL4 transcriptional activity, and ferroptosis markers were detected to assess the effects of ACSL4 gene lactylation on ferroptosis. The biological effects of exosomal LDHA in photoaged tissue were validated using an in vivo UVB-irradiated mouse model.

Results

UVB irradiation induced fibroblast senescence and significantly upregulated LDHA expression. Exosomes from senescent fibroblasts were effectively taken up by HaCaT cells, leading to increased lactate levels and enhanced histone H3K18 lactylation in recipient cells. LDHA knockdown or inhibition downregulated ACSL4 expression and suppressed ferroptosis, whereas exogenous lactate partially restored these effects. RNA sequencing and ChIP-qPCR results indicated that LDHA-mediated lactylation modification was enriched at the ACSL4 promoter region, enhancing its transcriptional activity. In vivo experiments further confirmed that senescent exosomes accelerated UVB-induced skin collagen degradation and ferroptosis, while LDHA intervention significantly alleviated photoaging damage.

Conclusion

Senescent fibroblast-derived exosomes deliver LDHA, promoting histone lactylation modification, which upregulates ACSL4 expression and activates the ferroptosis pathway, ultimately accelerating skin photoaging. This study reveals the coupling mechanism between metabolic signaling and epigenetic regulation in skin aging, providing new molecular targets and a theoretical basis for anti-photoaging therapy.