结直肠癌(CRC)释放肿瘤源型因子产生慢性炎症和营养不良，契合于中医脾虚证内涵。CRC分泌的HMGB1和ROS通过RAGE诱导肌肉自噬和有氧糖酵解，产生的酮体、乳酸、谷氨酰胺等代谢物供肿瘤细胞进行氧化磷酸化，其消耗肌肉、因癌致虚的反向瓦博格效应与“脾虚肌肉失养”的论述一致。我们发现，HMGB1通过PGAM5与RIPK2、PKM1的相互作用诱导肌肉细胞自噬和有氧糖酵解。基于此，我们提出假说：CRC通过RAGE及PGAM5通路诱导骨骼肌自噬和有氧糖酵解，致脾虚肌肉失养；CRC利用产生的谷氨酰胺等代谢物进行氧化磷酸化并加重脾虚。拟首先分析临床CRC脾虚病人能量代谢重编程与RAGE和PGAM5关系；再应用RAGE和PGAM5基因敲除小鼠阐明肿瘤诱导肌肉自噬和有氧糖酵解的机制，以参苓白术散反佐骨骼肌自噬与脾虚证关系；提炼CRC诱导骨骼肌自噬致脾虚肌肉失养的机制，有望提供脾主身之肌肉经典论述的新认识。

Colorectal cancer (CRC) induced malnutrition and even cachexia are important death causes. Spleen-deficiency is an important pathogenesis and a major clinic syndrome of CRC with malnutrition. CRC cells secrete reactive oxygen species (ROS) and high-mobility group box 1 (HMGB1) to drive autophagy and aerobic glycolysis of muscle cells. The “parasitic” metabolic coupling converts the muscle into a “factory” for the local production of recycled and high-energy nutrients (such as L-lactate) - to fuel oxidative mitochondrial metabolism of CRC cells. The reverse “Warburg effects” conform to the essense of Spleen-deficiency theory in traditional Chinese medicine. Our previous work showed that HMGB1 induces autophagy and aerobic glycolysis through interaction between PGAM5, RIPK2 and PKM1. We thus propose a hypothesis that CRC usurps glatamate, ketone and lactate from skeletal muscle as an energy repository through inducing skeletal muscles autophagy. To elucidate the hypothesis, the relationship between energy metabolism reprogramming and the internal essence of Spleen-deficiency in CRC patients would be analyzed. RAGE-/- and PGAM5-/- would be used to analyze the mechanism of skeletal muscles autophagy induced by CRC. Shenling Baizhu San would be used as a ounterevidence to explain the correlation between Spleen-deficiency and skeletal muscle autophagy. Finally, overexpression and siRNA would be used to elucidate the regulatory mechanism in cells. Novel connotation between skeletal muscle autophagy and Spleen -deficiency would be infused to the theory “Spleen governing muscles”.