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

Summary

Senescent fibroblast-derived exosomes deliver LDHA to recipient keratinocytes, elevating lactate and H3K18 lactylation at the ACSL4 promoter to drive ferroptosis and photoaging. Genetic and pharmacologic LDHA inhibition suppressed ACSL4 and ferroptosis, with partial rescue by exogenous lactate; in vivo UVB models confirmed mitigation of collagen loss with LDHA intervention.

Key Findings

• UVB induced fibroblast senescence with marked LDHA upregulation; senescent exosomes were internalized by HaCaT cells, increasing lactate and H3K18 lactylation.
• LDHA knockdown/inhibition reduced ACSL4 expression and ferroptosis, while exogenous lactate partially rescued these effects.
• ChIP-qPCR showed enrichment of H3K18 lactylation at the ACSL4 promoter, enhancing transcription.
• In vivo UVB models demonstrated that senescent exosomes accelerated collagen degradation and ferroptosis; LDHA intervention alleviated photoaging damage.

Clinical Implications

Although preclinical, the LDHA–lactylation–ACSL4 axis suggests testable interventions (e.g., topical LDHA inhibitors, ferroptosis blockers, exosome modulation) for photoaging; safety and efficacy require clinical evaluation.

Limitations

• No human clinical validation or biomarker correlation
• Focus on fibroblast-to-keratinocyte axis; other skin cell interactions were not assessed

Future Directions

Evaluate topical/systemic LDHA inhibitors or anti-lactylation strategies in human skin models and early-phase trials; map cell type–specific lactylation and ferroptosis in human photoaged skin.