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<p>Age-related hearing loss (ARHL) is a prevalent sensory deficit characterized by cochlear hair cell apoptosis, yet the underlying epigenetic mechanisms remain unclear. This study investigated the role of E2F1-mediated 53BP2 lactylation in ARHL pathogenesis using naturally aging C57BL/6J mice and HEI-OC1 cochlear hair cell-like cells. We found that E2F1 was significantly upregulated in aged cochleae, correlating with elevated ABR thresholds, hair cell loss, and apoptotic marker expression. In vitro, E2F1 overexpression promoted HEI-OC1 cell apoptosis by stabilizing p53, while E2F1 knockdown attenuated p53 accumulation and cell death under oxidative stress. Mechanistically, mass spectrometry identified 53BP2 lactylation at lysine 476 (K476), which was enhanced by E2F1. The K476R mutation abolished 53BP2-p53 binding, reduced p53 stability, and inhibited apoptosis. Further, E2F1 transcriptionally upregulated p300, a lactyltransferase that directly mediates 53BP2 K476 lactylation. p300 knockdown reversed E2F1-induced 53BP2 lactylation and p53-dependent apoptosis. These findings reveal a novel E2F1-p300-53BP2 lactylation-p53 signaling axis driving cochlear hair cell apoptosis in ARHL, highlighting potential therapeutic targets for age-related hearing loss.</p>

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E2F1-mediated 53BP2 lactylation stabilizes p53 to induce cochlear hair cell apoptosis in mouse age-related hearing loss

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月2日

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  • Xiaoqin Luo,
  • Jun Liu,
  • Chanyuan Zhang,
  • Wei Yuan,
  • Gang Qin

摘要

Age-related hearing loss (ARHL) is a prevalent sensory deficit characterized by cochlear hair cell apoptosis, yet the underlying epigenetic mechanisms remain unclear. This study investigated the role of E2F1-mediated 53BP2 lactylation in ARHL pathogenesis using naturally aging C57BL/6J mice and HEI-OC1 cochlear hair cell-like cells. We found that E2F1 was significantly upregulated in aged cochleae, correlating with elevated ABR thresholds, hair cell loss, and apoptotic marker expression. In vitro, E2F1 overexpression promoted HEI-OC1 cell apoptosis by stabilizing p53, while E2F1 knockdown attenuated p53 accumulation and cell death under oxidative stress. Mechanistically, mass spectrometry identified 53BP2 lactylation at lysine 476 (K476), which was enhanced by E2F1. The K476R mutation abolished 53BP2-p53 binding, reduced p53 stability, and inhibited apoptosis. Further, E2F1 transcriptionally upregulated p300, a lactyltransferase that directly mediates 53BP2 K476 lactylation. p300 knockdown reversed E2F1-induced 53BP2 lactylation and p53-dependent apoptosis. These findings reveal a novel E2F1-p300-53BP2 lactylation-p53 signaling axis driving cochlear hair cell apoptosis in ARHL, highlighting potential therapeutic targets for age-related hearing loss.