1. Significance of cancer cachexia.
Cancer cachexia is a multifactorial wasting syndrome characterized by progressive weight loss and persistent erosion of host cell mass in response to malignant growth. Cancer cachexia occurs in 50-80% of cancer patients and is an independent predictor of poor prognosis. Progressive loss of skeletal muscle mass contributes to progressive weight loss. Animal studies suggest that maintaining skeletal muscle mass reverses muscle wasting and prolongs survival. However, there are few treatments that preserve skeletal muscle mass as a treatment for cachexia. Certain cancers appear to have a predisposition to cause cachexia. However, the exact mechanisms involved in cachexia are largely unknown and no drug can be used to treat muscle wasting.

2. Current challenges in the treatment of muscle wasting.
Cancer cachexia is associated with reduced treatment tolerance, therapeutic response, quality of life, and survival. Nutritional support cannot reverse cancer cachexia syndrome, and drugs have been considered an effective approach. However, many drugs or treatments, including chemotherapy, targeted therapy, immunotherapy, and biological therapy, have contraindications for cancer cachexia. These contradictions hinder research and development in cancer cachexia. Focusing on the progressive loss of skeletal muscle mass, we found that multiple metabolic by-products accumulate due to excessive tumor growth and dysfunctional host metabolism. Metabolic alteration in cancer has been recognized as a plausible therapeutic target. We are therefore taking advantage of the metabolic reprogramming of specific cancers to explore metabolism-based anti-cachexia strategies.

3. Novelty of this work.
3.1 Metabolites mediated by genetic alterations contribute to cancer cachexia.

Metabolic reprogramming often occurs in cancer patients, and several metabolites and pathways are altered in cancer cachexia patients. Specific cancers appear to have distinct metabolic characteristics and a predisposition to induce cachexia. The present studies focus on the contribution of metabolites related to genetic alterations in the development of cancer cachexia. First, we collected all cachexia-related metabolites and oncometabolites. We then screened the active metabolites for the driver of proteolysis using a widely used in vitro myoblast differentiation model. Based on the functional annotation of oncogenes, the genetic alteration and metabolites were studied in tumors and myotubes to establish the metabolic microenvironment and evaluate the direct effect of metabolites on muscle atrophy. To elucidate the mechanism of genetic alteration-mediated metabolic reprogramming in the development of proteolysis, downstream metabolic enzymes were overexpressed and an oncogene inhibitor was used in in vitro and in vivo experiments. We aim to use metabolite rescue to delay or reverse the development of cancer cachexia syndrome.

3.2 Oncometabolites D2HG induced proteolysis.

The oncometabolite D2HG impaired myotube differentiation and induced proteolysis through NADPH-dependent pathways. We confirmed that D2HG induced muscle atrophy mainly through upregulation of the ubiquitinated proteasome pathway and reduced myotube diameter. D2hghdh encodes the mitochondrial enzyme D-2-hydroxyglutarate dehydrogenase, which can convert D2HG to 2-ketoglutarate. Overexpression of D2hghdh in well-differentiated myotubes could alleviate D2HG-induced proteolysis and myotube wasting by catalyzing the excess D2HG. The animal experiment showed that IDH1 mutation resulted in high serum D2HG concentration and also aggravated muscle wasting and cancer cachexia. The IDH1 inhibitor ivosidenib can inhibit the production of D2HG. When the IDH1 mutation cancer-bearing mouse was treated with ivosidenib, the cancer cachexia syndrome was alleviated and the cachexia process was delayed. The mechanism involved the mediator of D2HG, which links the interaction of tumor and skeletal muscle. Based on the metabolic changes in cancer, we are taking advantage of the metabolic reprogramming of specific cancers to explore metabolism-based anti-cachexia strategies.

3.3 Precision medicine treatment of cancer cachexia or malnutrition.

Based on the specific gene mutation-mediated distinct metabolite accumulation of D2HG, we found that a high concentration of D2HG in skeletal muscle leads to metabolic reprogramming and distinct transcriptional features. Catabolism of D2HG by overexpression of D2hghd and inhibition of the product of D2HG by the IDH1 mutation inhibitor ivosidenib could reverse the D2HG-mediated proteolysis effect and muscle atrophy. Individual treatment of cancer cachexia in IDH1 mutation patients was confirmed as catabolism of D2HG by IDH1 mutation inhibitor ivosidenib.