癌症恶病质及其相关并发症是有效癌症治疗的一大障碍，目前尚无法有效治疗。已经提出和测试了许多潜在的治疗方法，包括食欲刺激剂、靶向细胞因子阻断剂和营养补充剂等，但高效的治疗方法仍然缺乏。创新的癌症恶病质治疗方法是必要的。Kruppel样因子（KLF）家族在骨骼肌的发育、维持和新陈代谢中起到广泛而重要的作用。在KLF家族中，我们发现KLF10在许多恶化情况下上调表达，包括胰腺、肺部和结肠癌小鼠模型及人类患者中。随后，我们探究了KLF10功能缺失作为减轻与癌症相关的肌肉消耗的潜在策略。通过体内研究，利用将胰腺癌细胞正置植到野生型和KLF10基因敲除小鼠中，发现KLF10基因敲除小鼠能够显著保留瘦体重，并强烈抑制肌肉特异性蛋白质泛素连接酶Trim63和Fbxo32等与消耗有关的因子，以及与萎缩、钙信号和自噬有关的其他因子。生物信息学分析鉴定到转化生长因子β（TGF-β）是KLF10的主要上游调控因子，同时也是促进恶病质的因子。我们提供了直接的体内证据，表明KLF10基因敲除小鼠对TGF-β的萎缩效应具有抵抗力。基于染色质免疫沉淀（ChIP）的结合研究证明KLF10直接结合Trim63，一个已知与消耗相关的离化因子。综上所述，我们报告了TGF-β/KLF10轴在胰腺癌相关肌肉消耗的发病机制中起关键作用，并强调了以KLF10为靶标的策略作为预防肌肉消耗和限制癌症恶病质的有效手段。

Cancer cachexia, and its associated complications, represent a large and currently untreatable roadblock to effective cancer management. Many potential therapies have been proposed and tested-including appetite stimulants, targeted cytokine blockers, and nutritional supplementation-yet highly effective therapies are lacking. Innovative approaches to treating cancer cachexia are needed. Members of the Kruppel-like factor (KLF) family play wide-ranging and important roles in the development, maintenance, and metabolism of skeletal muscle. Within the KLF family, we identified KLF10 upregulation in a multitude of wasting contexts-including in pancreatic, lung, and colon cancer mouse models as well as in human patients. We subsequently interrogated loss-of-function of KLF10 as a potential strategy to mitigate cancer associated muscle wasting. In vivo studies leveraging orthotopic implantation of pancreas cancer cells into wild-type and KLF10 KO mice revealed significant preservation of lean mass and robust suppression of pro-atrophy muscle-specific ubiquitin ligases Trim63 and Fbxo32, as well as other factors implicated in atrophy, calcium signaling, and autophagy. Bioinformatics analyses identified Transforming growth factor beta (TGF-β), a known inducer of KLF10 and cachexia promoting factor, as a key upstream regulator of KLF10. We provide direct in vivo evidence that KLF10 KO mice are resistant to the atrophic effects of TGF-β. ChIP-based binding studies demonstrated direct binding to Trim63, a known wasting-associated atrogene. Taken together, we report a critical role for the TGF-β/KLF10 axis in the etiology of pancreatic cancer-associated muscle wasting and highlight the utility of targeting KLF10 as a strategy to prevent muscle wasting and limit cancer-associated cachexia.