Hand-foot syndrome (HFS) is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes. Even though the cause and pathophysiology of HFS are relatively widely reported, how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied. Additionally, prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce. In our study, we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS. Mechanistically, DNA damage, as the primary cytotoxic cause, in keratinocytes induces cell cycle arrest, activates the cGAS-STING signaling pathway, and subsequently mediates cellular senescence, ultimately fueling a robust secondary inflammatory response that results in HFS. More importantly, the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence. These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS.

手足综合征（HFS）是一种广泛认可的氟嘧啶化疗药物的剂量限制性皮肤毒性作用，会损害临床获益和治疗结果。尽管 HFS 的病因和病理生理学报道相对广泛，但氟嘧啶的毒性如何转化为持续性炎症尚未研究。此外，基于HFS发生和发展机制的预防和​​治疗策略也很少。在我们的研究中，我们证明cGAS-STING信号通路介导的细胞衰老在炎症反应中发挥着关键作用，并为HFS提供了治疗解决方案。从机制上讲，DNA 损伤作为主要的细胞毒性原因，在角质形成细胞中诱导细胞周期停滞，激活 cGAS-STING 信号通路，随后介导细胞衰老，最终引发强烈的继发炎症反应，导致 HFS。更重要的是，胸苷前药胸苷二乙酸酯被证明可以通过补偿胸苷酸缺陷来有效预防 HFS，从而促进 DNA 的复制和修复，从而避免细胞衰老。这些数据强调了 DNA 损伤介导的细胞衰老在 HFS 病因学中的重要性，并为氟嘧啶诱导的 HFS 提供了潜在的治疗锚点。